T cell receptor (TCR) signaling in health and disease
Tóm tắt
Interaction of the T cell receptor (TCR) with an MHC-antigenic peptide complex results in changes at the molecular and cellular levels in T cells. The outside environmental cues are translated into various signal transduction pathways within the cell, which mediate the activation of various genes with the help of specific transcription factors. These signaling networks propagate with the help of various effector enzymes, such as kinases, phosphatases, and phospholipases. Integration of these disparate signal transduction pathways is done with the help of adaptor proteins that are non-enzymatic in function and that serve as a scaffold for various protein–protein interactions. This process aids in connecting the proximal to distal signaling pathways, thereby contributing to the full activation of T cells. This review provides a comprehensive snapshot of the various molecules involved in regulating T cell receptor signaling, covering both enzymes and adaptors, and will discuss their role in human disease.
Từ khóa
Tài liệu tham khảo
Gorentla, B. K. & Zhong, X. P. T cell receptor signal transduction in T lymphocytes. J. Clin. Cell Immunol. 2012, 5 (2012).
Marshall, J. S., Warrington, R., Watson, W. & Kim, H. L. An introduction to immunology and immunopathology. Allergy Asthma Clin. Immunol. 14, 49 (2018).
Quang, C. T., Zaniboni, B. & Ghysdael, J. A TCR-switchable cell death pathway in T-ALL. Oncoscience 4, 17–18 (2017).
Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22, 745–763 (2004).
Samelson, L. E. Signal transduction mediated by the T cell antigen receptor: the role of adapter proteins. Annu. Rev. Immunol. 20, 371–394 (2002).
Hwang, J. R., Byeon, Y., Kim, D. & Park, S. G. Recent insights of T cell receptor-mediated signaling pathways for T cell activation and development. Exp. Mol. Med. 52, 750–761 (2020).
Courtney, A. H., Lo, W. L. & Weiss, A. TCR signaling: mechanisms of initiation and propagation. Trends Biochem. Sci. 43, 108–123 (2018).
Koretzky, G. A. & Boerth, N. J. The role of adapter proteins in T cell activation. Cell Mol. Life Sci. 56, 1048–1060 (1999).
Gerth, E. & Mattner, J. The role of adaptor proteins in the biology of natural killer T (NKT) cells. Front. Immunol. 10, 1449 (2019).
Wilkinson, B., Wang, H. & Rudd, C. E. Positive and negative adaptors in T-cell signalling. Immunology 111, 368–374 (2004).
Wucherpfennig, K. W. et al. Structural biology of the T-cell receptor: insights into receptor assembly, ligand recognition, and initiation of signaling. Cold Spring Harb. Perspect. Biol. 2, a005140 (2010).
Kuhns, M. S. & Badgandi, H. B. Piecing together the family portrait of TCR-CD3 complexes. Immunol. Rev. 250, 120–143 (2012).
Rast, J. P. et al. alpha, beta, gamma, and delta T cell antigen receptor genes arose early in vertebrate phylogeny. Immunity 6, 1–11 (1997).
Gaulard, P. et al. Expression of the alpha/beta and gamma/delta T-cell receptors in 57 cases of peripheral T-cell lymphomas. Identification of a subset of gamma/delta T-cell lymphomas. Am. J. Pathol. 137, 617–628 (1990).
Bruno, L., Fehling, H. J. & von Boehmer, H. The alpha beta T cell receptor can replace the gamma delta receptor in the development of gamma delta lineage cells. Immunity 5, 343–352 (1996).
Zhao, Y., Niu, C. & Cui, J. Gamma-delta (gammadelta) T cells: friend or foe in cancer development? J. Transl. Med. 16, 3 (2018).
van Boxel, G. I., Holmes, S., Fugger, L. & Jones, E. Y. An alternative conformation of the T-cell receptor alpha constant region. J. Mol. Biol. 400, 828–837 (2010).
Allison, T. J. et al. Structure of a human gammadelta T-cell antigen receptor. Nature 411, 820–824 (2001).
Touma, M. et al. The TCR C beta FG loop regulates alpha beta T cell development. J. Immunol. 176, 6812–6823 (2006).
Morath, A. & Schamel, W.W. Alphabeta and gammadelta T cell receptors: similar but different. J. Leukoc. Biol. 107, 1045–1055 (2020).
Dong et al. Structural basis of assembly of the human T cell receptor-CD3 complex. Nature 573, 546–552 (2019).
Alcover, A., Alarcon, B. & Di Bartolo, V. Cell biology of T cell receptor expression and regulation. Annu. Rev. Immunol. 36, 103–125 (2018).
Bach, F. H., Bach, M. L. & Sondel, P. M. Differential function of major histocompatibility complex antigens in T-lymphocyte activation. Nature 259, 273–281 (1976).
Cantor, H. & Boyse, E. A. Regulation of cellular and humoral immune responses by T-cell subclasses. Cold Spring Harb. Symp. Quant. Biol. 41, 23–32 (1977).
Shiku, H. et al. Expression of T-cell differentiation antigens on effector cells in cell-mediated cytotoxicity in vitro. Evidence for functional heterogeneity related to the surface phenotype of T cells. J. Exp. Med. 141, 227–241 (1975).
Ellmeier, W., Sawada, S. & Littman, D. R. The regulation of CD4 and CD8 coreceptor gene expression during T cell development. Annu. Rev. Immunol. 17, 523–554 (1999).
Ellmeier, W., Haust, L. & Tschismarov, R. Transcriptional control of CD4 and CD8 coreceptor expression during T cell development. Cell Mol. Life Sci. 70, 4537–4553 (2013).
Lustgarten, J., Waks, T. & Eshhar, Z. CD4 and CD8 accessory molecules function through interactions with major histocompatibility complex molecules which are not directly associated with the T cell receptor-antigen complex. Eur. J. Immunol. 21, 2507–2515 (1991).
Tikhonova, A. N. et al. Alphabeta T cell receptors that do not undergo major histocompatibility complex-specific thymic selection possess antibody-like recognition specificities. Immunity 36, 79–91 (2012).
Hernandez-Hoyos, G., Sohn, S. J., Rothenberg, E. V. & Alberola-Ila, J. Lck activity controls CD4/CD8 T cell lineage commitment. Immunity 12, 313–322 (2000).
Zamoyska, R. The CD8 coreceptor revisited: one chain good, two chains better. Immunity 1, 243–246 (1994).
Kim, S. V. & Flavell, R. A. Immunology. CD8alphaalpha and T cell memory. Science 304, 529–530 (2004).
Madakamutil, L. T. et al. CD8alphaalpha-mediated survival and differentiation of CD8 memory T cell precursors. Science 304, 590–593 (2004).
Wieczorek, M. et al. Major histocompatibility complex (MHC) class I and MHC class II proteins: conformational plasticity in antigen presentation. Front. Immunol. 8, 292 (2017).
Cohen, N. R., Garg, S. & Brenner, M. B. Antigen presentation by CD1 lipids, T cells, and NKT cells in microbial immunity. Adv. Immunol. 102, 1–94 (2009).
Jackman, R. M., Moody, D. B. & Porcelli, S. A. Mechanisms of lipid antigen presentation by CD1. Crit. Rev. Immunol. 19, 49–63 (1999).
Zhai, Y. et al. Src-family protein tyrosine kinases: a promising target for treating cardiovascular diseases. Int. J. Med. Sci. 18, 1216–1224 (2021).
Thomas, S. M. & Brugge, J. S. Cellular functions regulated by Src family kinases. Annu. Rev. Cell Dev. Biol. 13, 513–609 (1997).
Kazi, J. U. & Ronnstrand, L. The role of SRC family kinases in FLT3 signaling. Int. J. Biochem. Cell Biol. 107, 32–37 (2019).
Patwardhan, P. & Resh, M. D. Myristoylation and membrane binding regulate c-Src stability and kinase activity. Mol. Cell Biol. 30, 4094–4107 (2010).
Saksela, K. & Permi, P. SH3 domain ligand binding: what’s the consensus and where’s the specificity? FEBS Lett. 586, 2609–2614 (2012).
Kaneko, T., Joshi, R., Feller, S. M. & Li, S. S. Phosphotyrosine recognition domains: the typical, the atypical and the versatile. Cell Commun. Signal. 10, 32 (2012).
Bergman, M. et al. The human p50csk tyrosine kinase phosphorylates p56lck at Tyr-505 and down regulates its catalytic activity. EMBO J. 11, 2919–2924 (1992).
Mustelin, T. & Altman, A. Dephosphorylation and activation of the T cell tyrosine kinase pp56lck by the leukocyte common antigen (CD45). Oncogene 5, 809–813 (1990).
Yamaguchi, H. & Hendrickson, W. A. Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation. Nature 384, 484–489 (1996).
Bommhardt, U., Schraven, B. & Simeoni, L. Beyond TCR signaling: emerging functions of Lck in cancer and immunotherapy. Int. J. Mol. Sci. 20, 3500 (2019).
McNeill, L. et al. The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses. Immunity 27, 425–437 (2007).
Zikherman, J. et al. CD45-Csk phosphatase-kinase titration uncouples basal and inducible T cell receptor signaling during thymic development. Immunity 32, 342–354 (2010).
Wu, J. et al. Identification of substrates of human protein-tyrosine phosphatase PTPN22. J. Biol. Chem. 281, 11002–11010 (2006).
Chiang, G. G. & Sefton, B. M. Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase. J. Biol. Chem. 276, 23173–23178 (2001).
Huse, M. et al. Spatial and temporal dynamics of T cell receptor signaling with a photoactivatable agonist. Immunity 27, 76–88 (2007).
Molina, T. J. et al. Profound block in thymocyte development in mice lacking p56lck. Nature 357, 161–164 (1992).
van Oers, N. S., Killeen, N. & Weiss, A. Lck regulates the tyrosine phosphorylation of the T cell receptor subunits and ZAP-70 in murine thymocytes. J. Exp. Med. 183, 1053–1062 (1996).
Guirado, M. et al. Phosphorylation of the N-terminal and C-terminal CD3-epsilon-ITAM tyrosines is differentially regulated in T cells. Biochem. Biophys. Res. Commun. 291, 574–581 (2002).
Weiss, A. & Littman, D. R. Signal transduction by lymphocyte antigen receptors. Cell 76, 263–274 (1994).
Letourneur, F. & Klausner, R. D. A novel di-leucine motif and a tyrosine-based motif independently mediate lysosomal targeting and endocytosis of CD3 chains. Cell 69, 1143–1157 (1992).
Yao, X. R., Flaswinkel, H., Reth, M. & Scott, D. W. Immunoreceptor tyrosine-based activation motif is required to signal pathways of receptor-mediated growth arrest and apoptosis in murine B lymphoma cells. J. Immunol. 155, 652–661 (1995).
Bu, J. Y., Shaw, A. S. & Chan, A. C. Analysis of the interaction of ZAP-70 and syk protein-tyrosine kinases with the T-cell antigen receptor by plasmon resonance. Proc. Natl Acad. Sci. USA 92, 5106–5110 (1995).
Iwashima, M. et al. Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases. Science 263, 1136–1139 (1994).
Gascoigne, N. R., Casas, J., Brzostek, J. & Rybakin, V. Initiation of TCR phosphorylation and signal transduction. Front. Immunol. 2, 72 (2011).
Palacios, E. H. & Weiss, A. Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation. Oncogene 23, 7990–8000 (2004).
Stein, P. L., Lee, H. M., Rich, S. & Soriano, P. pp59fyn mutant mice display differential signaling in thymocytes and peripheral T cells. Cell 70, 741–750 (1992).
Appleby, M. W. et al. Defective T cell receptor signaling in mice lacking the thymic isoform of p59fyn. Cell 70, 751–763 (1992).
Straus, D. B. & Weiss, A. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Cell 70, 585–593 (1992).
Krystal, G. W., DeBerry, C. S., Linnekin, D. & Litz, J. Lck associates with and is activated by Kit in a small cell lung cancer cell line: inhibition of SCF-mediated growth by the Src family kinase inhibitor PP1. Cancer Res. 58, 4660–4666 (1998).
Marhall, A., Kazi, J. U. & Ronnstrand, L. The Src family kinase LCK cooperates with oncogenic FLT3/ITD in cellular transformation. Sci. Rep. 7, 13734 (2017).
Braunger, J. et al. Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site. Oncogene 14, 2619–2631 (1997).
Laugel, B. et al. Different T cell receptor affinity thresholds and CD8 coreceptor dependence govern cytotoxic T lymphocyte activation and tetramer binding properties. J. Biol. Chem. 282, 23799–23810 (2007).
Singer, A. & Bosselut, R. CD4/CD8 coreceptors in thymocyte development, selection, and lineage commitment: analysis of the CD4/CD8 lineage decision. Adv. Immunol. 83, 91–131 (2004).
Zamoyska, R. CD4 and CD8: modulators of T-cell receptor recognition of antigen and of immune responses? Curr. Opin. Immunol. 10, 82–87 (1998).
Janeway, C. A. Jr. The T cell receptor as a multicomponent signalling machine: CD4/CD8 coreceptors and CD45 in T cell activation. Annu. Rev. Immunol. 10, 645–674 (1992).
Veillette, A., Bookman, M. A., Horak, E. M. & Bolen, J. B. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell 55, 301–308 (1988).
Shaw, A. S. et al. The lck tyrosine protein kinase interacts with the cytoplasmic tail of the CD4 glycoprotein through its unique amino-terminal domain. Cell 59, 627–636 (1989).
Zlatkine, P., Mehul, B. & Magee, A. I. Retargeting of cytosolic proteins to the plasma membrane by the Lck protein tyrosine kinase dual acylation motif. J. Cell Sci. 110, 673–679 (1997).
Bijlmakers, M. J., Isobe-Nakamura, M., Ruddock, L. J. & Marsh, M. Intrinsic signals in the unique domain target p56(lck) to the plasma membrane independently of CD4. J. Cell Biol. 137, 1029–1040 (1997).
Yasuda, K. et al. Serine 6 of Lck tyrosine kinase: a critical site for Lck myristoylation, membrane localization, and function in T lymphocytes. J. Immunol. 165, 3226–3231 (2000).
Stephen, T. L., Wilson, B. S. & Laufer, T. M. Subcellular distribution of Lck during CD4 T-cell maturation in the thymic medulla regulates the T-cell activation threshold. Proc. Natl Acad. Sci. USA 109, 7415–7420 (2012).
Irvine, D. J., Purbhoo, M. A., Krogsgaard, M. & Davis, M. M. Direct observation of ligand recognition by T cells. Nature 419, 845–849 (2002).
Zimmermann, L. et al. Direct observation and quantitative analysis of Lck exchange between plasma membrane and cytosol in living T cells. J. Biol. Chem. 285, 6063–6070 (2010).
Akimzhanov, A. M. & Boehning, D. Rapid and transient palmitoylation of the tyrosine kinase Lck mediates Fas signaling. Proc. Natl Acad. Sci. USA 112, 11876–11880 (2015).
Shaw, A. S. et al. Short related sequences in the cytoplasmic domains of CD4 and CD8 mediate binding to the amino-terminal domain of the p56lck tyrosine protein kinase. Mol. Cell Biol. 10, 1853–1862 (1990).
Rudd, C. E. et al. The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes. Proc. Natl Acad. Sci. USA 85, 5190–5194 (1988).
Turner, J. M. et al. Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell 60, 755–765 (1990).
Lin, R. S., Rodriguez, C., Veillette, A. & Lodish, H. F. Zinc is essential for binding of p56(lck) to CD4 and CD8alpha. J. Biol. Chem. 273, 32878–32882 (1998).
Huse, M., Eck, M. J. & Harrison, S. C. A Zn2+ ion links the cytoplasmic tail of CD4 and the N-terminal region of Lck. J. Biol. Chem. 273, 18729–18733 (1998).
Kim, P. W. et al. A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8. Science 301, 1725–1728 (2003).
Wang, J. H. et al. Crystal structure of the human CD4 N-terminal two-domain fragment complexed to a class II MHC molecule. Proc. Natl Acad. Sci. USA 98, 10799–10804 (2001).
Yin, Y., Wang, X. X. & Mariuzza, R. A. Crystal structure of a complete ternary complex of T-cell receptor, peptide-MHC, and CD4. Proc. Natl Acad. Sci. USA 109, 5405–5410 (2012).
Wang, X. X. et al. Affinity maturation of human CD4 by yeast surface display and crystal structure of a CD4-HLA-DR1 complex. Proc. Natl Acad. Sci. USA 108, 15960–15965 (2011).
Li, Y., Yin, Y. & Mariuzza, R. A. Structural and biophysical insights into the role of CD4 and CD8 in T cell activation. Front. Immunol. 4, 206 (2013).
Gao, G. F. et al. Crystal structure of the complex between human CD8alpha(alpha) and HLA-A2. Nature 387, 630–634 (1997).
van der Merwe, P. A. & Davis, S. J. Molecular interactions mediating T cell antigen recognition. Annu. Rev. Immunol. 21, 659–684 (2003).
Kim, S. T. et al. The alphabeta T cell receptor is an anisotropic mechanosensor. J. Biol. Chem. 284, 31028–31037 (2009).
Kim, S. T. et al. Distinctive CD3 heterodimeric ectodomain topologies maximize antigen-triggered activation of alpha beta T cell receptors. J. Immunol. 185, 2951–2959 (2010).
Yoon, S. T., Dianzani, U., Bottomly, K. & Janeway, C. A. Jr. Both high and low avidity antibodies to the T cell receptor can have agonist or antagonist activity. Immunity 1, 563–569 (1994).
Devine, L., Kieffer, L. J., Aitken, V. & Kavathas, P. B. Human CD8 beta, but not mouse CD8 beta, can be expressed in the absence of CD8 alpha as a beta beta homodimer. J. Immunol. 164, 833–838 (2000).
Rybakin, V. et al. CD8alphaalpha and -alphabeta isotypes are equally recruited to the immunological synapse through their ability to bind to MHC class I. EMBO Rep. 12, 1251–1256 (2011).
Yachi, P. P., Ampudia, J., Gascoigne, N. R. & Zal, T. Nonstimulatory peptides contribute to antigen-induced CD8-T cell receptor interaction at the immunological synapse. Nat. Immunol. 6, 785–792 (2005).
Weyand, C. M., Goronzy, J. & Fathman, C. G. Modulation of CD4 by antigenic activation. J. Immunol. 138, 1351–1354 (1987).
Shin, J. et al. Structural features of the cytoplasmic region of CD4 required for internalization. EMBO J. 9, 425–434 (1990).
Sleckman, B. P. et al. Disruption of the CD4-p56lck complex is required for rapid internalization of CD4. Proc. Natl Acad. Sci. USA 89, 7566–7570 (1992).
Acres, R. B., Conlon, P. J., Mochizuki, D. Y. & Gallis, B. Rapid phosphorylation and modulation of the T4 antigen on cloned helper T cells induced by phorbol myristate acetate or antigen. J. Biol. Chem. 261, 16210–16214 (1986).
Pelchen-Matthews, A. et al. The protein tyrosine kinase p56lck inhibits CD4 endocytosis by preventing entry of CD4 into coated pits. J. Cell Biol. 117, 279–290 (1992).
Stepanek, O. et al. Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance. Cell 159, 333–345 (2014).
Barber, E. K. et al. The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex. Proc. Natl Acad. Sci. USA 86, 3277–3281 (1989).
Burgess, K. E. et al. Biochemical identification of a direct physical interaction between the CD4:p56lck and Ti(TcR)/CD3 complexes. Eur. J. Immunol. 21, 1663–1668 (1991).
Weissman, A. M. et al. Tyrosine phosphorylation of the human T cell antigen receptor zeta-chain: activation via CD3 but not CD2. J. Immunol. 141, 3532–3536 (1988).
Monostori, E. et al. Activation of human T lymphocytes via the CD2 antigen results in tyrosine phosphorylation of T cell antigen receptor zeta-chains. J. Immunol. 144, 1010–1014 (1990).
Kersh, E. N., Shaw, A. S. & Allen, P. M. Fidelity of T cell activation through multistep T cell receptor zeta phosphorylation. Science 281, 572–575 (1998).
Housden, H. R. et al. Investigation of the kinetics and order of tyrosine phosphorylation in the T-cell receptor zeta chain by the protein tyrosine kinase Lck. Eur. J. Biochem. 270, 2369–2376 (2003).
Isakov, N. et al. ZAP-70 binding specificity to T cell receptor tyrosine-based activation motifs: the tandem SH2 domains of ZAP-70 bind distinct tyrosine-based activation motifs with varying affinity. J. Exp. Med. 181, 375–380 (1995).
Xu, C. et al. Regulation of T cell receptor activation by dynamic membrane binding of the CD3epsilon cytoplasmic tyrosine-based motif. Cell 135, 702–713 (2008).
Deford-Watts, L. M. et al. The cytoplasmic tail of the T cell receptor CD3 epsilon subunit contains a phospholipid-binding motif that regulates T cell functions. J. Immunol. 183, 1055–1064 (2009).
Aivazian, D. & Stern, L. J. Phosphorylation of T cell receptor zeta is regulated by a lipid dependent folding transition. Nat. Struct. Biol. 7, 1023–1026 (2000).
Huyer, G. et al. Mechanism of inhibition of protein-tyrosine phosphatases by vanadate and pervanadate. J. Biol. Chem. 272, 843–851 (1997).
Gagnon, E. et al. Response multilayered control of T cell receptor phosphorylation. Cell 142, 669–671 (2010).
Xu, X., Li, H. & Xu, C. Structural understanding of T cell receptor triggering. Cell Mol. Immunol. 17, 193–202 (2020).
Shi, X. et al. Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids. Nature 493, 111–115 (2013).
Li, F. Y. et al. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature 475, 471–476 (2011).
Lioudyno, M. I. et al. Orai1 and STIM1 move to the immunological synapse and are up-regulated during T cell activation. Proc. Natl Acad. Sci. USA 105, 2011–2016 (2008).
Sigalov, A. B., Aivazian, D. A., Uversky, V. N. & Stern, L. J. Lipid-binding activity of intrinsically unstructured cytoplasmic domains of multichain immune recognition receptor signaling subunits. Biochemistry 45, 15731–15739 (2006).
van Oers, N. S., Killeen, N. & Weiss, A. ZAP-70 is constitutively associated with tyrosine-phosphorylated TCR zeta in murine thymocytes and lymph node T cells. Immunity 1, 675–685 (1994).
van Oers, N. S. et al. Constitutive tyrosine phosphorylation of the T-cell receptor (TCR) zeta subunit: regulation of TCR-associated protein tyrosine kinase activity by TCR zeta. Mol. Cell Biol. 13, 5771–5780 (1993).
Dorfman, J. R., Stefanova, I., Yasutomo, K. & Germain, R. N. CD4+ T cell survival is not directly linked to self-MHC-induced TCR signaling. Nat. Immunol. 1, 329–335 (2000).
Chakraborty, A. K. & Weiss, A. Insights into the initiation of TCR signaling. Nat. Immunol. 15, 798–807 (2014).
Wei, Q. et al. Lck bound to coreceptor is less active than free Lck. Proc. Natl Acad. Sci. USA 117, 15809–15817 (2020).
Jiang, N. et al. Two-stage cooperative T cell receptor-peptide major histocompatibility complex-CD8 trimolecular interactions amplify antigen discrimination. Immunity 34, 13–23 (2011).
Casas, J. et al. Ligand-engaged TCR is triggered by Lck not associated with CD8 coreceptor. Nat. Commun. 5, 5624 (2014).
Ike, H. et al. Mechanism of Lck recruitment to the T-cell receptor cluster as studied by single-molecule-fluorescence video imaging. Chemphyschem 4, 620–626 (2003).
Horkova, V. et al. Dynamics of the coreceptor-LCK interactions during T cell development shape the self-reactivity of peripheral CD4 and CD8 T cells. Cell Rep. 30, 1504–1514 e1507 (2020).
Li, L. et al. Ionic CD3-Lck interaction regulates the initiation of T-cell receptor signaling. Proc. Natl Acad. Sci. USA 114, E5891–E5899 (2017).
Wang, H. et al. ZAP-70: an essential kinase in T-cell signaling. Cold Spring Harb. Perspect. Biol. 2, a002279 (2010).
Neumeister, E. N. et al. Binding of ZAP-70 to phosphorylated T-cell receptor zeta and eta enhances its autophosphorylation and generates specific binding sites for SH2 domain-containing proteins. Mol. Cell Biol. 15, 3171–3178 (1995).
Beach, D. et al. Dual role of SLP-76 in mediating T cell receptor-induced activation of phospholipase C-gamma1. J. Biol. Chem. 282, 2937–2946 (2007).
Zhong, X. P. et al. Diacylglycerol kinases in immune cell function and self-tolerance. Immunol. Rev. 224, 249–264 (2008).
Berridge, M. J. Inositol trisphosphate and calcium signalling mechanisms. Biochim. Biophys. Acta 1793, 933–940 (2009).
Kania, E. et al. IP3 receptor-mediated calcium signaling and its role in autophagy in cancer. Front. Oncol. 7, 140 (2017).
Vig, M. et al. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312, 1220–1223 (2006).
Penna, A. et al. The CRAC channel consists of a tetramer formed by Stim-induced dimerization of Orai dimers. Nature 456, 116–120 (2008).
Weidinger, C., Shaw, P. J. & Feske, S. STIM1 and STIM2-mediated Ca(2+) influx regulates antitumour immunity by CD8(+) T cells. EMBO Mol. Med. 5, 1311–1321 (2013).
Zhang, S. L. et al. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437, 902–905 (2005).
Macian, F. NFAT proteins: key regulators of T-cell development and function. Nat. Rev. Immunol. 5, 472–484 (2005).
Macian, F. et al. Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109, 719–731 (2002).
Zha, Y. et al. T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-alpha. Nat. Immunol. 7, 1166–1173 (2006).
Olenchock, B. A. et al. Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nat. Immunol. 7, 1174–1181 (2006).
Savignac, M., Mellstrom, B. & Naranjo, J. R. Calcium-dependent transcription of cytokine genes in T lymphocytes. Pflugers Arch. 454, 523–533 (2007).
Le Deist, F. et al. A primary T-cell immunodeficiency associated with defective transmembrane calcium influx. Blood 85, 1053–1062 (1995).
Feske, S. et al. Severe combined immunodeficiency due to defective binding of the nuclear factor of activated T cells in T lymphocytes of two male siblings. Eur. J. Immunol. 26, 2119–2126 (1996).
Joseph, N., Reicher, B. & Barda-Saad, M. The calcium feedback loop and T cell activation: how cytoskeleton networks control intracellular calcium flux. Biochim Biophys. Acta 1838, 557–568 (2014).
Parker, P. J. et al. Equivocal, explicit and emergent actions of PKC isoforms in cancer. Nat. Rev. Cancer. 21, 51–63 (2020).
Kabir, N. N., Rönnstrand, L. & Kazi, J. U. Protein kinase C expression is deregulated in chronic lymphocytic leukemia. Leuk. Lymphoma 54, 2288–2290 (2013).
Kazi, J. U., Kabir, N. N. & Rönnstrand, L. Protein kinase C (PKC) as a drug target in chronic lymphocytic leukemia. Med. Oncol. 30, 757 (2013).
Pfeifhofer-Obermair, C., Thuille, N. & Baier, G. Involvement of distinct PKC gene products in T cell functions. Front. Immunol. 3, 220 (2012).
Szamel, M. & Resch, K. T-cell antigen receptor-induced signal-transduction pathways-activation and function of protein kinases C in T lymphocytes. Eur. J. Biochem. 228, 1–15 (1995).
Blanchett, S., Boal-Carvalho, I., Layzell, S. & Seddon, B. NF-kappaB and extrinsic cell death pathways—entwined do-or-die decisions for T cells. Trends Immunol. 42, 76–88 (2020).
Matsumoto, M. et al. Essential role of NF-kappa B-inducing kinase in T cell activation through the TCR/CD3 pathway. J. Immunol. 169, 1151–1158 (2002).
Yamagishi, M. W. & New, T. Paradigm of T cell signaling: learning from malignancies. J. Clin. Cell Immunol. S12, 007 (2012).
Lu, H. Y. et al. The CBM-opathies—a rapidly expanding spectrum of human inborn errors of immunity caused by mutations in the CARD11-BCL10-MALT1 complex. Front. Immunol. 9, 2078 (2018).
Matsumoto, R. et al. Phosphorylation of CARMA1 plays a critical role in T cell receptor-mediated NF-kappaB activation. Immunity 23, 575–585 (2005).
Weil, R. & Israel, A. Deciphering the pathway from the TCR to NF-kappaB. Cell Death Differ. 13, 826–833 (2006).
Sun, L. et al. The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol. Cell 14, 289–301 (2004).
Zhou, H. et al. Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature 427, 167–171 (2004).
Hayden, M. S., West, A. P. & Ghosh, S. NF-kappaB and the immune response. Oncogene 25, 6758–6780 (2006).
Hoffmann, A., Natoli, G. & Ghosh, G. Transcriptional regulation via the NF-kappaB signaling module. Oncogene 25, 6706–6716 (2006).
So, T. & Croft, M. Regulation of the PKCtheta-NF-kappaB axis in T lymphocytes by the tumor necrosis factor receptor family member OX40. Front. Immunol. 3, 133 (2012).
Schulze-Luehrmann, J. & Ghosh, S. Antigen-receptor signaling to nuclear factor kappa B. Immunity 25, 701–715 (2006).
Krappmann, D. et al. Molecular mechanisms of constitutive NF-kappaB/Rel activation in Hodgkin/Reed-Sternberg cells. Oncogene 18, 943–953 (1999).
Staudt, L. M. Oncogenic activation of NF-kappaB. Cold Spring Harb. Perspect. Biol. 2, a000109 (2010).
Krishna, S. et al. Chronic activation of the kinase IKKbeta impairs T cell function and survival. J. Immunol. 189, 1209–1219 (2012).
Smith-Garvin, J. E., Koretzky, G. A. & Jordan, M. S. T cell activation. Annu. Rev. Immunol. 27, 591–619 (2009).
Ebinu, J. O. et al. RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs. Science 280, 1082–1086 (1998).
Janknecht, R., Ernst, W. H., Pingoud, V. & Nordheim, A. Activation of ternary complex factor Elk-1 by MAP kinases. EMBO J. 12, 5097–5104 (1993).
Kolch, W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat. Rev. Mol. Cell Biol. 6, 827–837 (2005).
Jia, H. et al. Ras-ERK1/2 signaling accelerates the progression of colorectal cancer via mediation of H2BK5ac. Life Sci. 230, 89–96 (2019).
Bertin, S. et al. Dual-specificity phosphatase 6 regulates CD4+ T-cell functions and restrains spontaneous colitis in IL-10-deficient mice. Mucosal Immunol. 8, 505–515 (2015).
Damasio, M. P. et al. Extracellular signal-regulated kinase (ERK) pathway control of CD8+ T cell differentiation. Biochem. J. 478, 79–98 (2020).
Kaminuma, O. et al. Vav-Rac1-mediated activation of the c-Jun N-terminal kinase/c-Jun/AP-1 pathway plays a major role in stimulation of the distal NFAT site in the interleukin-2 gene promoter. Mol. Cell Biol. 21, 3126–3136 (2001).
Chung, J., Uchida, E., Grammer, T. C. & Blenis, J. STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol. Cell Biol. 17, 6508–6516 (1997).
Rohrs, J. A., Siegler, E. L., Wang, P. & Finley, S. D. ERK activation in CAR T cells is amplified by CD28-mediated increase in CD3zeta phosphorylation. iScience 23, 101023 (2020).
Dower, N. A. et al. RasGRP is essential for mouse thymocyte differentiation and TCR signaling. Nat. Immunol. 1, 317–321 (2000).
Shen, S. et al. Critical roles of RasGRP1 for invariant NKT cell development. J. Immunol. 187, 4467–4473 (2011).
Chen, Y. et al. Differential requirement of RasGRP1 for gammadelta T cell development and activation. J. Immunol. 189, 61–71 (2012).
Gorentla, B. K., Wan, C. K. & Zhong, X. P. Negative regulation of mTOR activation by diacylglycerol kinases. Blood 117, 4022–4031 (2011).
Mor, A., Philips, M. R. & Pillinger, M. H. The role of Ras signaling in lupus T lymphocytes: biology and pathogenesis. Clin. Immunol. 125, 215–223 (2007).
Rincon, M., Flavell, R. A. & Davis, R. J. Signal transduction by MAP kinases in T lymphocytes. Oncogene 20, 2490–2497 (2001).
Rincon, M. & Davis, R. J. Regulation of the immune response by stress-activated protein kinases. Immunol. Rev. 228, 212–224 (2009).
Dodeller, F. et al. The p38 mitogen-activated protein kinase regulates effector functions of primary human CD4 T cells. Eur. J. Immunol. 35, 3631–3642 (2005).
Conze, D. et al. c-Jun NH(2)-terminal kinase (JNK)1 and JNK2 have distinct roles in CD8(+) T cell activation. J. Exp. Med. 195, 811–823 (2002).
Dong, C. et al. Defective T cell differentiation in the absence of Jnk1. Science 282, 2092–2095 (1998).
Canovas, B. & Nebreda, A. R. Diversity and versatility of p38 kinase signalling in health and disease. Nat. Rev. Mol. Cell Biol. 22, 346–366 (2021).
Bogoyevitch, M. A. et al. c-Jun N-terminal kinase (JNK) signaling: recent advances and challenges. Biochim. Biophys. Acta 1804, 463–475 (2010).
Bellon, S. et al. The structure of phosphorylated p38gamma is monomeric and reveals a conserved activation-loop conformation. Structure 7, 1057–1065 (1999).
Salvador, J. M. et al. Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases. Nat. Immunol. 6, 390–395 (2005).
Giardino Torchia, M. L. et al. Intensity and duration of TCR signaling is limited by p38 phosphorylation of ZAP-70(T293) and destabilization of the signalosome. Proc. Natl Acad. Sci. USA 115, 2174–2179 (2018).
Blonska, M. & Lin, X. CARMA1-mediated NF-kappaB and JNK activation in lymphocytes. Immunol. Rev. 228, 199–211 (2009).
Blonska, M. et al. The CARMA1-Bcl10 signaling complex selectively regulates JNK2 kinase in the T cell receptor-signaling pathway. Immunity 26, 55–66 (2007).
Sinclair, L. V. et al. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat. Immunol. 9, 513–521 (2008).
Chi, H. Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12, 325–338 (2012).
Delgoffe, G. M. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12, 295–303 (2011).
Lee, K. et al. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32, 743–753 (2010).
Pollizzi, K. N. & Powell, J. D. Regulation of T cells by mTOR: the known knowns and the known unknowns. Trends Immunol. 36, 13–20 (2015).
Hamilton, K. S. et al. T cell receptor-dependent activation of mTOR signaling in T cells is mediated by Carma1 and MALT1, but not Bcl10. Sci. Signal 7, ra55 (2014).
Nakaya, M. et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40, 692–705 (2014).
Liu, C. et al. mTOR and metabolic regulation of conventional and regulatory T cells. J. Leukoc. Biol. 97, 837–847 (2015).
Procaccini, C. & Matarese, G. Regulatory T cells, mTOR kinase, and metabolic activity. Cell Mol. Life Sci. 69, 3975–3987 (2012).
Pierdominici, M., Vacirca, D., Delunardo, F. & Ortona, E. mTOR signaling and metabolic regulation of T cells: new potential therapeutic targets in autoimmune diseases. Curr. Pharm. Des. 17, 3888–3897 (2011).
Xia, F. et al. TCR and CD28 concomitant stimulation elicits a distinctive calcium response in naive T cells. Front. Immunol. 9, 2864 (2018).
Narayan, P., Holt, B., Tosti, R. & Kane, L. P. CARMA1 is required for Akt-mediated NF-kappaB activation in T cells. Mol. Cell Biol. 26, 2327–2336 (2006).
Park, S. G. et al. The kinase PDK1 integrates T cell antigen receptor and CD28 coreceptor signaling to induce NF-kappaB and activate T cells. Nat. Immunol. 10, 158–166 (2009).
Ishimaru, N., Kishimoto, H., Hayashi, Y. & Sprent, J. Regulation of naive T cell function by the NF-kappaB2 pathway. Nat. Immunol. 7, 763–772 (2006).
Turner, M. & Billadeau, D. D. VAV proteins as signal integrators for multi-subunit immune-recognition receptors. Nat. Rev. Immunol. 2, 476–486 (2002).
Hehner, S. P. et al. Tyrosine-phosphorylated Vav1 as a point of integration for T-cell receptor- and CD28-mediated activation of JNK, p38, and interleukin-2 transcription. J. Biol. Chem. 275, 18160–18171 (2000).
Singh, M. D. et al. B cell adaptor for PI3-kinase (BCAP) modulates CD8(+) effector and memory T cell differentiation. J. Exp. Med. 215, 2429–2443 (2018).
Zhang, W. et al. LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92, 83–92 (1998).
Bubeck Wardenburg, J. et al. Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. J. Biol. Chem. 271, 19641–19644 (1996).
Sommers, C. L., Samelson, L. E. & Love, P. E. LAT: a T lymphocyte adapter protein that couples the antigen receptor to downstream signaling pathways. Bioessays 26, 61–67 (2004).
Koretzky, G. A., Abtahian, F. & Silverman, M. A. SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond. Nat. Rev. Immunol. 6, 67–78 (2006).
Resh, M. D. Myristylation and palmitylation of Src family members: the fats of the matter. Cell 76, 411–413 (1994).
van’t Hof, W. & Resh, M. D. Rapid plasma membrane anchoring of newly synthesized p59fyn: selective requirement for NH2-terminal myristoylation and palmitoylation at cysteine-3. J. Cell Biol. 136, 1023–1035 (1997).
Kabouridis, P. S., Magee, A. I. & Ley, S. C. S-acylation of LCK protein tyrosine kinase is essential for its signalling function in T lymphocytes. EMBO J. 16, 4983–4998 (1997).
Xavier, R. et al. Membrane compartmentation is required for efficient T cell activation. Immunity 8, 723–732 (1998).
Montixi, C. et al. Engagement of T cell receptor triggers its recruitment to low-density detergent-insoluble membrane domains. EMBO J. 17, 5334–5348 (1998).
Duplay, P., Thome, M., Herve, F. & Acuto, O. p56lck interacts via its src homology 2 domain with the ZAP-70 kinase. J. Exp. Med. 179, 1163–1172 (1994).
Pelosi, M. et al. Tyrosine 319 in the interdomain B of ZAP-70 is a binding site for the Src homology 2 domain of Lck. J. Biol. Chem. 274, 14229–14237 (1999).
Ho, K. C. et al. CBAP promotes thymocyte negative selection by facilitating T-cell receptor proximal signaling. Cell Death Dis. 5, e1518 (2014).
Chiang, Y. J. et al. CBAP modulates Akt-dependent TSC2 phosphorylation to promote Rheb-mTORC1 signaling and growth of T-cell acute lymphoblastic leukemia. Oncogene 38, 1432–1447 (2019).
June, C. H., Fletcher, M. C., Ledbetter, J. A. & Samelson, L. E. Increases in tyrosine phosphorylation are detectable before phospholipase C activation after T cell receptor stimulation. J. Immunol. 144, 1591–1599 (1990).
Zhang, W., Trible, R. P. & Samelson, L. E. LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation. Immunity 9, 239–246 (1998).
Zhang, W. et al. Association of Grb2, Gads, and phospholipase C-gamma 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell angigen receptor-mediated signaling. J. Biol. Chem. 275, 23355–23361 (2000).
Williams, B. L. et al. Phosphorylation of Tyr319 in ZAP-70 is required for T-cell antigen receptor-dependent phospholipase C-gamma1 and Ras activation. EMBO J. 18, 1832–1844 (1999).
Deckert, M. et al. Adaptor function for the Syk kinases-interacting protein 3BP2 in IL-2 gene activation. Immunity 9, 595–605 (1998).
Lindholm, C. K. et al. Requirement of the Src homology 2 domain protein Shb for T cell receptor-dependent activation of the interleukin-2 gene nuclear factor for activation of T cells element in Jurkat T cells. J. Biol. Chem. 274, 28050–28057 (1999).
Williams, B. L. et al. Genetic evidence for differential coupling of Syk family kinases to the T-cell receptor: reconstitution studies in a ZAP-70-deficient Jurkat T-cell line. Mol. Cell Biol. 18, 1388–1399 (1998).
Finco, T. S. et al. LAT is required for TCR-mediated activation of PLCgamma1 and the Ras pathway. Immunity 9, 617–626 (1998).
Zhang, W. et al. Functional analysis of LAT in TCR-mediated signaling pathways using a LAT-deficient Jurkat cell line. Int. Immunol. 11, 943–950 (1999).
Kazi, J. U. & Rönnstrand, L. FMS-like tyrosine kinase 3/FLT3: from basic science to clinical implications. Physiol. Rev. 99, 1433–1466 (2019).
Chougule, R. A. et al. Expression of GADS enhances FLT3-induced mitogenic signaling. Oncotarget 7, 14112–14124 (2016).
Sommers, C. L. et al. Mutation of the phospholipase C-gamma1-binding site of LAT affects both positive and negative thymocyte selection. J. Exp. Med. 201, 1125–1134 (2005).
Ravichandran, K. S., Lorenz, U., Shoelson, S. E. & Burakoff, S. J. Interaction of Shc with Grb2 regulates association of Grb2 with mSOS. Mol. Cell Biol. 15, 593–600 (1995).
Joazeiro, C. A. et al. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science 286, 309–312 (1999).
Liu, S. K., Fang, N., Koretzky, G. A. & McGlade, C. J. The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors. Curr. Biol. 9, 67–75 (1999).
Liu, Z. G., Hsu, H., Goeddel, D. V. & Karin, M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell 87, 565–576 (1996).
Yoder, J. et al. Requirement for the SLP-76 adaptor GADS in T cell development. Science 291, 1987–1991 (2001).
Clements, J. L. et al. SLP-76 expression is restricted to hemopoietic cells of monocyte, granulocyte, and T lymphocyte lineage and is regulated during T cell maturation and activation. J. Immunol. 161, 3880–3889 (1998).
Yablonski, D., Kadlecek, T. & Weiss, A. Identification of a phospholipase C-gamma1 (PLC-gamma1) SH3 domain-binding site in SLP-76 required for T-cell receptor-mediated activation of PLC-gamma1 and NFAT. Mol. Cell Biol. 21, 4208–4218 (2001).
Lin, J. & Weiss, A. Identification of the minimal tyrosine residues required for linker for activation of T cell function. J. Biol. Chem. 276, 29588–29595 (2001).
Kumar, L. et al. Differential role of SLP-76 domains in T cell development and function. Proc. Natl Acad. Sci. USA 99, 884–889 (2002).
Motto, D. G. et al. Implication of the GRB2-associated phosphoprotein SLP-76 in T cell receptor-mediated interleukin 2 production. J. Exp. Med. 183, 1937–1943 (1996).
Musci, M. A. et al. Three domains of SLP-76 are required for its optimal function in a T cell line. J. Immunol. 159, 1639–1647 (1997).
Pivniouk, V. et al. Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76. Cell 94, 229–238 (1998).
Clements, J. L. et al. Requirement for the leukocyte-specific adapter protein SLP-76 for normal T cell development. Science 281, 416–419 (1998).
Bubeck Wardenburg, J. et al. Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76. Immunity 9, 607–616 (1998).
Su, Y. W. et al. Interaction of SLP adaptors with the SH2 domain of Tec family kinases. Eur. J. Immunol. 29, 3702–3711 (1999).
Bunnell, S. C. et al. Biochemical interactions integrating Itk with the T cell receptor-initiated signaling cascade. J. Biol. Chem. 275, 2219–2230 (2000).
Griffiths, E. K. et al. Positive regulation of T cell activation and integrin adhesion by the adapter Fyb/Slap. Science 293, 2260–2263 (2001).
Peterson, E. J. et al. Coupling of the TCR to integrin activation by Slap-130/Fyb. Science 293, 2263–2265 (2001).
Nishibe, S. et al. Increase of the catalytic activity of phospholipase C-gamma 1 by tyrosine phosphorylation. Science 250, 1253–1256 (1990).
Atherly, L. O. et al. The Tec family tyrosine kinases Itk and Rlk regulate the development of conventional CD8+ T cells. Immunity 25, 79–91 (2006).
Readinger, J. A. et al. Tec kinases regulate T-lymphocyte development and function: new insights into the roles of Itk and Rlk/Txk. Immunol. Rev. 228, 93–114 (2009).
Liu, K. Q., Bunnell, S. C., Gurniak, C. B. & Berg, L. J. T cell receptor-initiated calcium release is uncoupled from capacitative calcium entry in Itk-deficient T cells. J. Exp. Med. 187, 1721–1727 (1998).
Schaeffer, E. M. et al. Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity. Science 284, 638–641 (1999).
Sommers, C. L. et al. A role for the Tec family tyrosine kinase Txk in T cell activation and thymocyte selection. J. Exp. Med. 190, 1427–1438 (1999).
Shan, X. & Wange, R. L. Itk/Emt/Tsk activation in response to CD3 cross-linking in Jurkat T cells requires ZAP-70 and Lat and is independent of membrane recruitment. J. Biol. Chem. 274, 29323–29330 (1999).
Sela, M. et al. Sequential phosphorylation of SLP-76 at tyrosine 173 is required for activation of T and mast cells. EMBO J. 30, 3160–3172 (2011).
Granum, S. et al. The kinase Itk and the adaptor TSAd change the specificity of the kinase Lck in T cells by promoting the phosphorylation of Tyr192. Sci. Signal. 7, ra118 (2014).
Bogin, Y., Ainey, C., Beach, D. & Yablonski, D. SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK. Proc. Natl Acad. Sci. USA 104, 6638–6643 (2007).
Sanzone, S. et al. SLAM-associated protein deficiency causes imbalanced early signal transduction and blocks downstream activation in T cells from X-linked lymphoproliferative disease patients. J. Biol. Chem. 278, 29593–29599 (2003).
Veillette, A. et al. Importance and mechanism of ‘switch’ function of SAP family adapters. Immunol. Rev. 232, 229–239 (2009).
Sayos, J. et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462–469 (1998).
Shlapatska, L. M. et al. CD150 association with either the SH2-containing inositol phosphatase or the SH2-containing protein tyrosine phosphatase is regulated by the adaptor protein SH2D1A. J. Immunol. 166, 5480–5487 (2001).
Chen, S. & Dong, Z. NK cell recognition of hematopoietic cells by SLAM-SAP families. Cell Mol. Immunol. 16, 452–459 (2019).
Cannons, J. L. et al. Biochemical and genetic evidence for a SAP-PKC-theta interaction contributing to IL-4 regulation. J. Immunol. 185, 2819–2827 (2010).
Gu, C. et al. The X-linked lymphoproliferative disease gene product SAP associates with PAK-interacting exchange factor and participates in T cell activation. Proc. Natl Acad. Sci. USA 103, 14447–14452 (2006).
Latour, S. et al. Binding of SAP SH2 domain to FynT SH3 domain reveals a novel mechanism of receptor signalling in immune regulation. Nat. Cell Biol. 5, 149–154 (2003).
Li, C., Schibli, D. & Li, S. S. The XLP syndrome protein SAP interacts with SH3 proteins to regulate T cell signaling and proliferation. Cell Signal. 21, 111–119 (2009).
Proust, R., Bertoglio, J. & Gesbert, F. The adaptor protein SAP directly associates with CD3zeta chain and regulates T cell receptor signaling. PLoS ONE 7, e43200 (2012).
Canna, S. W. & Marsh, R. A. Pediatric hemophagocytic lymphohistiocytosis. Blood 135, 1332–1343 (2020).
Panchal, N., Booth, C., Cannons, J. L. & Schwartzberg, P. L. X-Linked lymphoproliferative disease type 1: a clinical and molecular perspective. Front. Immunol. 9, 666 (2018).
Snow, A. L. et al. Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency. J. Clin. Invest. 119, 2976–2989 (2009).
Zheng, L., Li, J. & Lenardo, M. Restimulation-induced cell death: new medical and research perspectives. Immunol. Rev. 277, 44–60 (2017).
Snow, A. L. et al. The power and the promise of restimulation-induced cell death in human immune diseases. Immunol. Rev. 236, 68–82 (2010).
ElTanbouly, M. A. & Noelle, R. J. Rethinking peripheral T cell tolerance: checkpoints across a T cell’s journey. Nat. Rev. Immunol. 21, 257–267 (2021).
Brdicka, T. et al. Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase csk and is involved in regulation of T cell activation. J. Exp. Med. 191, 1591–1604 (2000).
Kawabuchi, M. et al. Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Nature 404, 999–1003 (2000).
Takeuchi, S. et al. Transmembrane phosphoprotein Cbp positively regulates the activity of the carboxyl-terminal Src kinase, Csk. J. Biol. Chem. 275, 29183–29186 (2000).
Torgersen, K. M. et al. Release from tonic inhibition of T cell activation through transient displacement of C-terminal Src kinase (Csk) from lipid rafts. J. Biol. Chem. 276, 29313–29318 (2001).
Davidson, D. et al. Phosphorylation-dependent regulation of T-cell activation by PAG/Cbp, a lipid raft-associated transmembrane adaptor. Mol. Cell Biol. 23, 2017–2028 (2003).
Salmond, R. J. et al. T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and tolerance. Immunol. Rev. 228, 9–22 (2009).
Marie-Cardine, A. et al. SHP2-interacting transmembrane adaptor protein (SIT), a novel disulfide-linked dimer regulating human T cell activation. J. Exp. Med. 189, 1181–1194 (1999).
Hubener, C. et al. Complete sequence, genomic organization, and chromosomal localization of the human gene encoding the SHP2-interacting transmembrane adaptor protein (SIT). Immunogenetics 53, 337–341 (2001).
Pfrepper, K. I. et al. Structural and functional dissection of the cytoplasmic domain of the transmembrane adaptor protein SIT (SHP2-interacting transmembrane adaptor protein). Eur. J. Immunol. 31, 1825–1836 (2001).
Nagaishi, T. et al. SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms. Immunity 25, 769–781 (2006).
Lorenz, U. S. H. P.-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunol. Rev. 228, 342–359 (2009).
Stefanova, I. et al. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat. Immunol. 4, 248–254 (2003).
Caunt, C. J. et al. Spatiotemporal regulation of ERK2 by dual specificity phosphatases. J. Biol. Chem. 283, 26612–26623 (2008).
Stambolic, V. et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95, 29–39 (1998).
Shulga, Y. V., Topham, M. K. & Epand, R. M. Regulation and functions of diacylglycerol kinases. Chem. Rev. 111, 6186–6208 (2011).
Sim, J. A., Kim, J. & Yang, D. Beyond lipid signaling: pleiotropic effects of diacylglycerol kinases in cellular signaling. Int. J. Mol. Sci. 21, 6861 (2020).
Zhong, X. P. et al. Regulation of T cell receptor-induced activation of the Ras-ERK pathway by diacylglycerol kinase zeta. J. Biol. Chem. 277, 31089–31098 (2002).
Carrasco, S. & Merida, I. Diacylglycerol-dependent binding recruits PKCtheta and RasGRP1 C1 domains to specific subcellular localizations in living T lymphocytes. Mol. Biol. Cell 15, 2932–2942 (2004).
Riese, M. J., Moon, E. K., Johnson, B. D. & Albelda, S. M. Diacylglycerol kinases (DGKs): novel targets for improving T cell activity in cancer. Front. Cell Dev. Biol. 4, 108 (2016).
Zhong, X. P. et al. Enhanced T cell responses due to diacylglycerol kinase zeta deficiency. Nat. Immunol. 4, 882–890 (2003).
Zhong, X. P., Olenchock, B. A. & Koretzky, G. A. The role of diacylglycerol kinases in T cell anergy. Ernst Schering Found. Symp. Proc. 139–149 (2007).
Guo, R. et al. Synergistic control of T cell development and tumor suppression by diacylglycerol kinase alpha and zeta. Proc. Natl Acad. Sci. USA 105, 11909–11914 (2008).
Baldanzi, G. et al. SAP-mediated inhibition of diacylglycerol kinase alpha regulates TCR-induced diacylglycerol signaling. J. Immunol. 187, 5941–5951 (2011).
Booth, C. et al. X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood 117, 53–62 (2011).
Ruffo, E. et al. Inhibition of diacylglycerol kinase alpha restores restimulation-induced cell death and reduces immunopathology in XLP-1. Sci. Transl. Med 8, 321ra327 (2016).
Buetow, L. & Huang, D. T. Structural insights into the catalysis and regulation of E3 ubiquitin ligases. Nat. Rev. Mol. Cell Biol. 17, 626–642 (2016).
Heissmeyer, V. et al. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat. Immunol. 5, 255–265 (2004).
Scharschmidt, E. et al. Degradation of Bcl10 induced by T-cell activation negatively regulates NF-kappa B signaling. Mol. Cell Biol. 24, 3860–3873 (2004).
Gao, M. et al. Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science 306, 271–275 (2004).
Liu, Y. C. The E3 ubiquitin ligase Itch in T cell activation, differentiation, and tolerance. Semin. Immunol. 19, 197–205 (2007).
Naramura, M. et al. c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nat. Immunol. 3, 1192–1199 (2002).
Wang, H. Y. et al. Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70. J. Biol. Chem. 276, 26004–26011 (2001).
Murphy, M. A. et al. Tissue hyperplasia and enhanced T-cell signalling via ZAP-70 in c-Cbl-deficient mice. Mol. Cell Biol. 18, 4872–4882 (1998).
Fournel, M., Davidson, D., Weil, R. & Veillette, A. Association of tyrosine protein kinase Zap-70 with the protooncogene product p120c-cbl in T lymphocytes. J. Exp. Med. 183, 301–306 (1996).
Lupher, M. L. Jr. et al. A novel phosphotyrosine-binding domain in the N-terminal transforming region of Cbl interacts directly and selectively with ZAP-70 in T cells. J. Biol. Chem. 271, 24063–24068 (1996).
Ota, Y. et al. Characterization of Cbl tyrosine phosphorylation and a Cbl-Syk complex in RBL-2H3 cells. J. Exp. Med. 184, 1713–1723 (1996).
Bachmaier, K. et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403, 211–216 (2000).
Hartley, D. & Corvera, S. Formation of c-Cbl.phosphatidylinositol 3-kinase complexes on lymphocyte membranes by a p56lck-independent mechanism. J. Biol. Chem. 271, 21939–21943 (1996).
Knudsen, B. S., Feller, S. M. & Hanafusa, H. Four proline-rich sequences of the guanine-nucleotide exchange factor C3G bind with unique specificity to the first Src homology 3 domain of Crk. J. Biol. Chem. 269, 32781–32787 (1994).
Tanaka, S. et al. C3G, a guanine nucleotide-releasing protein expressed ubiquitously, binds to the Src homology 3 domains of CRK and GRB2/ASH proteins. Proc. Natl Acad. Sci. USA 91, 3443–3447 (1994).
Gotoh, T. et al. Identification of Rap1 as a target for the Crk SH3 domain-binding guanine nucleotide-releasing factor C3G. Mol. Cell Biol. 15, 6746–6753 (1995).
Buday, L. et al. Interactions of Cbl with two adapter proteins, Grb2 and Crk, upon T cell activation. J. Biol. Chem. 271, 6159–6163 (1996).
Reedquist, K. A. et al. Stimulation through the T cell receptor induces Cbl association with Crk proteins and the guanine nucleotide exchange protein C3G. J. Biol. Chem. 271, 8435–8442 (1996).
Ichiba, T. et al. Enhancement of guanine-nucleotide exchange activity of C3G for Rap1 by the expression of Crk, CrkL, and Grb2. J. Biol. Chem. 272, 22215–22220 (1997).
Ohashi, Y. et al. T cell receptor-mediated tyrosine phosphorylation of Cas-L, a 105-kDa Crk-associated substrate-related protein, and its association of Crk and C3G. J. Biol. Chem. 273, 6446–6451 (1998).
Katagiri, K. et al. Rap1 is a potent activation signal for leukocyte function-associated antigen 1 distinct from protein kinase C and phosphatidylinositol-3-OH kinase. Mol. Cell Biol. 20, 1956–1969 (2000).
Tanaka, S., Ouchi, T. & Hanafusa, H. Downstream of Crk adaptor signaling pathway: activation of Jun kinase by v-Crk through the guanine nucleotide exchange protein C3G. Proc. Natl Acad. Sci. USA 94, 2356–2361 (1997).
Shao, Y., Elly, C. & Liu, Y. C. Negative regulation of Rap1 activation by the Cbl E3 ubiquitin ligase. EMBO Rep. 4, 425–431 (2003).
Zhang, W. et al. Negative regulation of T cell antigen receptor-mediated Crk-L-C3G signaling and cell adhesion by Cbl-b. J. Biol. Chem. 278, 23978–23983 (2003).
Uemura, N. et al. Involvement of the adapter protein CRKL in integrin-mediated adhesion. Oncogene 18, 3343–3353 (1999).
van der Donk, L. E. H. et al. Separate signaling events control TCR downregulation and T cell activation in primary human T cells. Immun. Inflamm. Dis. 9, 223–238 (2020).
Dustin, M. L. & Cooper, J. A. The immunological synapse and the actin cytoskeleton: molecular hardware for T cell signaling. Nat. Immunol. 1, 23–29 (2000).
Monks, C. R. et al. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82–86 (1998).
Grakoui, A. et al. The immunological synapse: a molecular machine controlling T cell activation. Science 285, 221–227 (1999).
Johnson, K. G., Bromley, S. K., Dustin, M. L. & Thomas, M. L. A supramolecular basis for CD45 tyrosine phosphatase regulation in sustained T cell activation. Proc. Natl Acad. Sci. USA 97, 10138–10143 (2000).
Bunnell, S. C. et al. Dynamic actin polymerization drives T cell receptor-induced spreading: a role for the signal transduction adaptor LAT. Immunity 14, 315–329 (2001).
Tuosto, L., Michel, F. & Acuto, O. p95vav associates with tyrosine-phosphorylated SLP-76 in antigen-stimulated T cells. J. Exp. Med. 184, 1161–1166 (1996).
Wunderlich, L., Farago, A., Downward, J. & Buday, L. Association of Nck with tyrosine-phosphorylated SLP-76 in activated T lymphocytes. Eur. J. Immunol. 29, 1068–1075 (1999).
Wang, H. et al. ADAP-SLP-76 binding differentially regulates supramolecular activation cluster (SMAC) formation relative to T cell-APC conjugation. J. Exp. Med. 200, 1063–1074 (2004).
Rohatgi, R. et al. The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly. Cell 97, 221–231 (1999).
Fischer, K. D. et al. Vav is a regulator of cytoskeletal reorganization mediated by the T-cell receptor. Curr. Biol. 8, 554–562 (1998).
Holsinger, L. J. et al. Defects in actin-cap formation in Vav-deficient mice implicate an actin requirement for lymphocyte signal transduction. Curr. Biol. 8, 563–572 (1998).
Wulfing, C., Bauch, A., Crabtree, G. R. & Davis, M. M. The vav exchange factor is an essential regulator in actin-dependent receptor translocation to the lymphocyte-antigen-presenting cell interface. Proc. Natl Acad. Sci. USA 97, 10150–10155 (2000).
O’Rourke, L. M. et al. CD19 as a membrane-anchored adaptor protein of B lymphocytes: costimulation of lipid and protein kinases by recruitment of Vav. Immunity 8, 635–645 (1998).
Snapper, S. B. & Rosen, F. S. The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization. Annu. Rev. Immunol. 17, 905–929 (1999).
Snapper, S. B. et al. Wiskott-Aldrich syndrome protein-deficient mice reveal a role for WASP in T but not B cell activation. Immunity 9, 81–91 (1998).
Zhang, J. et al. Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott-Aldrich syndrome protein-deficient lymphocytes. J. Exp. Med. 190, 1329–1342 (1999).
Higgs, H. N. & Pollard, T. D. Regulation of actin polymerization by Arp2/3 complex and WASp/Scar proteins. J. Biol. Chem. 274, 32531–32534 (1999).
Mullins, R. D. How WASP-family proteins and the Arp2/3 complex convert intracellular signals into cytoskeletal structures. Curr. Opin. Cell Biol. 12, 91–96 (2000).
Rivero-Lezcano, O. M., Marcilla, A., Sameshima, J. H. & Robbins, K. C. Wiskott-Aldrich syndrome protein physically associates with Nck through Src homology 3 domains. Mol. Cell Biol. 15, 5725–5731 (1995).
Zeng, R. et al. SLP-76 coordinates Nck-dependent Wiskott-Aldrich syndrome protein recruitment with Vav-1/Cdc42-dependent Wiskott-Aldrich syndrome protein activation at the T cell-APC contact site. J. Immunol. 171, 1360–1368 (2003).
Pauker, M. H. et al. Studying the dynamics of SLP-76, Nck, and Vav1 multimolecular complex formation in live human cells with triple-color FRET. Sci. Signal. 5, rs3 (2012).
Barda-Saad, M. et al. Cooperative interactions at the SLP-76 complex are critical for actin polymerization. EMBO J. 29, 2315–2328 (2010).
Hem, C. D. et al. T cell specific adaptor protein (TSAd) promotes interaction of Nck with Lck and SLP-76 in T cells. Cell Commun. Signal. 13, 31 (2015).
Buday, L., Wunderlich, L. & Tamas, P. The Nck family of adapter proteins: regulators of actin cytoskeleton. Cell Signal. 14, 723–731 (2002).
Lettau, M., Pieper, J. & Janssen, O. Nck adapter proteins: functional versatility in T cells. Cell Commun. Signal. 7, 1 (2009).
Berge, T. et al. T cell specific adapter protein (TSAd) interacts with Tec kinase ITK to promote CXCL12 induced migration of human and murine T cells. PLoS ONE 5, e9761 (2010).
Lettau, M. et al. The adapter protein Nck: role of individual SH3 and SH2 binding modules for protein interactions in T lymphocytes. Protein Sci. 19, 658–669 (2010).
Labelle-Cote, M. et al. Nck2 promotes human melanoma cell proliferation, migration and invasion in vitro and primary melanoma-derived tumor growth in vivo. BMC Cancer 11, 443 (2011).
da Silva, A. J. et al. Cloning of a novel T-cell protein FYB that binds FYN and SH2-domain-containing leukocyte protein 76 and modulates interleukin 2 production. Proc. Natl Acad. Sci. USA 94, 7493–7498 (1997).
Raab, M. et al. FYN-T-FYB-SLP-76 interactions define a T-cell receptor zeta/CD3-mediated tyrosine phosphorylation pathway that up-regulates interleukin 2 transcription in T-cells. J. Biol. Chem. 274, 21170–21179 (1999).
Geng, L., Raab, M. & Rudd, C. E. Cutting edge: SLP-76 cooperativity with FYB/FYN-T in the Up-regulation of TCR-driven IL-2 transcription requires SLP-76 binding to FYB at Tyr595 and Tyr651. J. Immunol. 163, 5753–5757 (1999).
Hunter, A. J. et al. Cutting edge: a novel function for the SLAP-130/FYB adapter protein in beta 1 integrin signaling and T lymphocyte migration. J. Immunol. 164, 1143–1147 (2000).
Wang, H. et al. SKAP-55 regulates integrin adhesion and formation of T cell-APC conjugates. Nat. Immunol. 4, 366–374 (2003).
Romero, S., Le Clainche, C. & Gautreau, A. M. Actin polymerization downstream of integrins: signaling pathways and mechanotransduction. Biochem. J. 477, 1–21 (2020).
Krause, M. et al. Fyn-binding protein (Fyb)/SLP-76-associated protein (SLAP), Ena/vasodilator-stimulated phosphoprotein (VASP) proteins and the Arp2/3 complex link T cell receptor (TCR) signaling to the actin cytoskeleton. J. Cell Biol. 149, 181–194 (2000).
Liu, J. et al. FYB (FYN binding protein) serves as a binding partner for lymphoid protein and FYN kinase substrate SKAP55 and a SKAP55-related protein in T cells. Proc. Natl Acad. Sci. USA 95, 8779–8784 (1998).
Marie-Cardine, A. et al. Molecular cloning of SKAP55, a novel protein that associates with the protein tyrosine kinase p59fyn in human T-lymphocytes. J. Biol. Chem. 272, 16077–16080 (1997).
Wu, L., Yu, Z. & Shen, S. H. SKAP55 recruits to lipid rafts and positively mediates the MAPK pathway upon T cell receptor activation. J. Biol. Chem. 277, 40420–40427 (2002).
Birge, R. B., Kalodimos, C., Inagaki, F. & Tanaka, S. Crk and CrkL adaptor proteins: networks for physiological and pathological signaling. Cell Commun. Signal 7, 13 (2009).
Gelkop, S. et al. Involvement of crk adapter proteins in regulation of lymphoid cell functions. Immunol. Res. 28, 79–91 (2003).
Feller, S. M. Crk family adaptors-signalling complex formation and biological roles. Oncogene 20, 6348–6371 (2001).
Kumar, S., Fajardo, J. E., Birge, R. B. & Sriram, G. Crk at the quarter century mark: perspectives in signaling and cancer. J. Cell Biochem. 115, 819–825 (2014).
Bitar, M. et al. Evaluating STAT5 phosphorylation as a mean to assess T cell proliferation. Front. Immunol. 10, 722 (2019).
Jones, N. et al. Akt and STAT5 mediate naive human CD4+ T-cell early metabolic response to TCR stimulation. Nat. Commun. 10, 2042 (2019).
Braiman, A. & Isakov, N. The role of Crk adaptor proteins in T-cell adhesion and migration. Front. Immunol. 6, 509 (2015).
Kung, C. et al. Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease. Nat. Med. 6, 343–345 (2000).
Tchilian, E. Z. et al. A deletion in the gene encoding the CD45 antigen in a patient with SCID. J. Immunol. 166, 1308–1313 (2001).
Wilkinson, B., Downey, J. S. & Rudd, C. E. T-cell signalling and immune system disorders. Expert Rev. Mol. Med. 7, 1–29 (2005).
Sawabe, T. et al. Defect of lck in a patient with common variable immunodeficiency. Int. J. Mol. Med. 7, 609–614 (2001).
Goldman, F. D. et al. Defective expression of p56lck in an infant with severe combined immunodeficiency. J. Clin. Invest. 102, 421–429 (1998).
Elder, M. E. et al. Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science 264, 1596–1599 (1994).
Arpaia, E. et al. Defective T cell receptor signaling and CD8+ thymic selection in humans lacking zap-70 kinase. Cell 76, 947–958 (1994).
Berg, L., Ronnelid, J., Klareskog, L. & Bucht, A. Down-regulation of the T cell receptor CD3 zeta chain in rheumatoid arthritis (RA) and its influence on T cell responsiveness. Clin. Exp. Immunol. 120, 174–182 (2000).
Takeuchi, T. et al. CD3 zeta defects in systemic lupus erythematosus. Ann. Rheum. Dis. 71(Suppl. 2), i78–i81 (2012).
Sakaguchi, N. et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426, 454–460 (2003).
Svojgr, K. et al. The adaptor protein NTAL enhances proximal signaling and potentiates corticosteroid-induced apoptosis in T-ALL. Exp. Hematol. 40, 379–385 (2012).
Svojgr, K. et al. Adaptor molecules expression in normal lymphopoiesis and in childhood leukemia. Immunol. Lett. 122, 185–192 (2009).
Lemonnier, F. & Mak, T. W. Activating TCR Signaling to Thwart T-ALL. Cancer Discov. 6, 946–948 (2016).
Wang, L. et al. Genomic profiling of Sezary syndrome identifies alterations of key T cell signaling and differentiation genes. Nat. Genet. 47, 1426–1434 (2015).
Kataoka, K. et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat. Genet. 47, 1304–1315 (2015).
Van Vlierberghe, P. & Ferrando, A. The molecular basis of T cell acute lymphoblastic leukemia. J. Clin. Invest. 122, 3398–3406 (2012).
Trinquand, A. et al. Triggering the TCR developmental checkpoint activates a therapeutically targetable tumor suppressive pathway in T-cell leukemia. Cancer Discov. 6, 972–985 (2016).
Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12, 269–281 (2012).
Southam, C. M., Brunschwig, A., Levin, A. G. & Dizon, Q. S. Effect of leukocytes on transplantability of human cancer. Cancer 19, 1743–1753 (1966).
Geukes Foppen, M. H., Donia, M., Svane, I. M. & Haanen, J. B. Tumor-infiltrating lymphocytes for the treatment of metastatic cancer. Mol. Oncol. 9, 1918–1935 (2015).
Perica, K., Varela, J. C., Oelke, M. & Schneck, J. Adoptive T cell immunotherapy for cancer. Rambam Maimonides Med. J. 6, e0004 (2015).
Axelrod, M. L., Cook, R. S., Johnson, D. B. & Balko, J. M. Biological consequences of MHC-II expression by tumor cells in cancer. Clin. Cancer Res. 25, 2392–2402 (2019).
Jena, B., Dotti, G. & Cooper, L. J. Redirecting T-cell specificity by introducing a tumor-specific chimeric antigen receptor. Blood 116, 1035–1044 (2010).
Dembic, Z. et al. Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature 320, 232–238 (1986).
Gross, G., Waks, T. & Eshhar, Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc. Natl Acad. Sci. USA 86, 10024–10028 (1989).
Mazumder, A. & Rosenberg, S. A. Successful immunotherapy of natural killer-resistant established pulmonary melanoma metastases by the intravenous adoptive transfer of syngeneic lymphocytes activated in vitro by interleukin 2. J. Exp. Med. 159, 495–507 (1984).
Rosenberg, S. A., Spiess, P. & Lafreniere, R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233, 1318–1321 (1986).
Andersen, R. et al. T cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression. Ann. Oncol. 29, 1575–1581 (2018).
Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).
Tran, E. et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 350, 1387–1390 (2015).
Tran, E. et al. T-cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 375, 2255–2262 (2016).
Zacharakis, N. et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat. Med. 24, 724–730 (2018).
Benmebarek, M. R. et al. Killing mechanisms of chimeric antigen receptor (CAR) T cells. Int. J. Mol. Sci. 20, 1283 (2019).
Morgan, R. A. et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).
Chodon, T. et al. Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. Clin. Cancer Res. 20, 2457–2465 (2014).
Johnson, L. A. et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114, 535–546 (2009).
Robbins, P. F. et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 29, 917–924 (2011).
Rapoport, A. P. et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat. Med. 21, 914–921 (2015).
Maio, M. Melanoma as a model tumour for immuno-oncology. Ann. Oncol. 23, viii10–viii14 (2012). Suppl 8.
Brentjens, R. J. et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat. Med. 9, 279–286 (2003).
Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).
Maude, S. L., Teachey, D. T., Porter, D. L. & Grupp, S. A. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood 125, 4017–4023 (2015).
Porter, D. L. et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med. 7, 303ra139 (2015).
Porter, D. L. et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).
Neelapu, S. S. et al. Axicabtagene Ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).
Cappell, K. M. et al. Long-term follow-up of anti-cd19 chimeric antigen receptor T-cell therapy. J. Clin. Oncol. 38, 3805–3815 (2020).
Boyiadzis, M. M. et al. Chimeric antigen receptor (CAR) T therapies for the treatment of hematologic malignancies: clinical perspective and significance. J. Immunother. Cancer 6, 137 (2018).
Fry, T. J. et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat. Med. 24, 20–28 (2018).
Cohen, A. D. et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J. Clin. Invest. 129, 2210–2221 (2019).
Sellner, L. et al. B-cell maturation antigen-specific chimeric antigen receptor T cells for multiple myeloma: clinical experience and future perspectives. Int. J. Cancer 147, 2029–2041 (2020).
Shah, N. et al. B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia 34, 985–1005 (2020).
Yu, Y. D. & Kim, T. J. Chimeric antigen receptor-engineered T cell therapy for the management of patients with metastatic prostate cancer: a comprehensive review. Int. J. Mol. Sci. 22, 640 (2021).
Wang, Y. et al. CD133-directed CAR T cells for advanced metastasis malignancies: a phase I trial. Oncoimmunology 7, e1440169 (2018).
Faramand, R. et al. Tumor microenvironment composition and severe cytokine release syndrome (crs) influence toxicity in patients with large B-cell lymphoma treated with Axicabtagene Ciloleucel. Clin. Cancer Res. 26, 4823–4831 (2020).
Seimetz, D., Heller, K. & Richter, J. Approval of first CAR-Ts: have we solved all hurdles for ATMPs? Cell Med. 11, 2155179018822781 (2019).
Siegler, E. L. & Kenderian, S. S. Neurotoxicity and cytokine release syndrome after chimeric antigen receptor T cell therapy: insights into mechanisms and novel therapies. Front. Immunol. 11, 1973 (2020).
Tully, S. et al. Impact of increasing wait times on overall mortality of chimeric antigen receptor T-cell therapy in large B-cell lymphoma: a discrete event simulation model. JCO Clin. Cancer Inf. 3, 1–9 (2019).
Rotte, A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J. Exp. Clin. Cancer Res 38, 255 (2019).
Cohen, E. E. W. et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 393, 156–167 (2019).
Hargadon, K. M., Johnson, C. E. & Williams, C. J. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int. Immunopharmacol. 62, 29–39 (2018).
Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540–1550 (2016).
Powles, T. et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 391, 748–757 (2018).
Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).
Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).
Schmid, P. et al. Atezolizumab and Nab-Paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379, 2108–2121 (2018).
Mahoney, K. M., Freeman, G. J. & McDermott, D. F. The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. Clin. Ther. 37, 764–782 (2015).
Makuku, R. et al. Current and future perspectives of PD-1/PDL-1 blockade in cancer immunotherapy. J. Immunol. Res. 2021, 6661406 (2021).
Zhao, B., Zhao, H. & Zhao, J. Efficacy of PD-1/PD-L1 blockade monotherapy in clinical trials. Ther. Adv. Med Oncol. 12, 1758835920937612 (2020).
Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
Liu, R., Liao, Y. Z., Zhang, W. & Zhou, H. H. Relevance of immune infiltration and clinical outcomes in pancreatic ductal adenocarcinoma subtypes. Front. Oncol. 10, 575264 (2020).
Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).
Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 20, 1370–1385 (2019).
Wolchok, J. D. et al. Overall survival with combined Nivolumab and Ipilimumab in advanced melanoma. N. Engl. J. Med 377, 1345–1356 (2017).
Kunert, A. & Debets, R. Engineering T cells for adoptive therapy: outsmarting the tumor. Curr. Opin. Immunol. 51, 133–139 (2018).
Yang, Y. et al. Myeloid-derived suppressor cells in tumors: from mechanisms to antigen specificity and microenvironmental regulation. Front. Immunol. 11, 1371 (2020).
Paluskievicz, C. M. et al. T regulatory cells and priming the suppressive tumor microenvironment. Front. Immunol. 10, 2453 (2019).
Anderson, K. G., Stromnes, I. M. & Greenberg, P. D. Obstacles posed by the tumor microenvironment to T cell activity: a case for synergistic therapies. Cancer Cell 31, 311–325 (2017).
Zhuang, Y., Liu, C., Liu, J. & Li, G. Resistance mechanism of PD-1/PD-L1 blockade in the cancer-immunity cycle. Onco Targets Ther. 13, 83–94 (2020).
Staveley-O’Carroll, K. et al. Induction of antigen-specific T cell anergy: an early event in the course of tumor progression. Proc. Natl Acad. Sci. USA 95, 1178–1183 (1998).
Hodi, F. S. et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc. Natl Acad. Sci. USA 105, 3005–3010 (2008).
Liakou, C. I. et al. CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc. Natl Acad. Sci. USA 105, 14987–14992 (2008).
Romano, E. et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc. Natl Acad. Sci. USA 112, 6140–6145 (2015).
Tarhini, A. A. et al. Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS ONE 9, e87705 (2014).
Sharma, A. et al. Anti-CTLA-4 immunotherapy does not deplete FOXP3(+) regulatory T cells (Tregs) in human cancers. Clin. Cancer Res. 25, 1233–1238 (2019).
Arce Vargas, F. et al. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell. 33, 649–663 e644 (2018).
Huard, B. et al. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes. Eur. J. Immunol. 24, 3216–3221 (1994).
Puhr, H. C. & Ilhan-Mutlu, A. New emerging targets in cancer immunotherapy: the role of LAG3. ESMO Open 4, e000482 (2019).
Kantarjian, H. et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N. Engl. J. Med. 376, 836–847 (2017).
de Oliveira, C. E. et al. CCR5-dependent homing of T regulatory cells to the tumor microenvironment contributes to skin squamous cell carcinoma development. Mol. Cancer Ther. 16, 2871–2880 (2017).
Pylayeva-Gupta, Y. et al. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21, 836–847 (2012).
Chapman, N. M., Connolly, S. F., Reinl, E. L. & Houtman, J. C. Focal adhesion kinase negatively regulates Lck function downstream of the T cell antigen receptor. J. Immunol. 191, 6208–6221 (2013).
Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).
Hollingsworth, R. E. & Jansen, K. Turning the corner on therapeutic cancer vaccines. NPJ Vaccines 4, 7 (2019).
Kinkead, H. L. et al. Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer. JCI Insight 3, (2018).
Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).
Zhu, G. et al. Albumin/vaccine nanocomplexes that assemble in vivo for combination cancer immunotherapy. Nat. Commun. 8, 1954 (2017).
Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).
Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565, 234–239 (2019).
Kandalaft, L. E. et al. Autologous lysate-pulsed dendritic cell vaccination followed by adoptive transfer of vaccine-primed ex vivo co-stimulated T cells in recurrent ovarian cancer. Oncoimmunology 2, e22664 (2013).
Ribas, A. et al. Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma. Clin. Cancer Res 15, 6267–6276 (2009).