SHP-1 and SHP-2 Associate with Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation

Journal of Immunology - Tập 173 Số 2 - Trang 945-954 - 2004
Jens M. Chemnitz1, Richard V. Parry1, Kim E. Nichols2, Carl H. June1, James L. Riley1
1*Abramson Family Cancer Research Institute and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and
2†Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104

Tóm tắt

Abstract To study the cis- and trans-acting factors that mediate programmed death 1 (PD-1) signaling in primary human CD4 T cells, we constructed a chimeric molecule consisting of the murine CD28 extracellular domain and human PD-1 cytoplasmic tail. When introduced into CD4 T cells, this construct mimics the activity of endogenous PD-1 in terms of its ability to suppress T cell expansion and cytokine production. The cytoplasmic tail of PD-1 contains two structural motifs, an ITIM and an immunoreceptor tyrosine-based switch motif (ITSM). Mutation of the ITIM had little effect on PD-1 signaling or functional activity. In contrast, mutation of the ITSM abrogated the ability of PD-1 to block cytokine synthesis and to limit T cell expansion. Further biochemical analyses revealed that the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.

Từ khóa


Tài liệu tham khảo

Carreno, B. M., M. Collins. 2003. BTLA: a new inhibitory receptor with a B7-like ligand. Trends Immunol. 24:524.

Rudd, C. E., H. Schneider. 2003. Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat. Rev. Immunol. 3:544.

Chuang, E., T. S. Fisher, R. W. Morgan, M. D. Robbins, J. M. Duerr, M. G. Vander Heiden, J. P. Gardner, J. E. Hambor, M. J. Neveu, C. B. Thompson. 2000. The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A. Immunity 13:313.

Truitt, K. E., C. M. Hicks, J. B. Imboden. 1994. Stimulation of CD28 triggers an association between CD28 and phosphatidylinositol 3-kinase in Jurkat T cells. J. Exp. Med. 179:1071.

Schneider, H., Y. C. Cai, K. V. Prasad, S. E. Shoelson, C. E. Rudd. 1995. T cell antigen CD28 binds to the GRB-2/SOS complex, regulators of p21ras. Eur. J. Immunol. 25:1044.

August, A., B. DuPont. 1994. CD28 of T lymphocytes associates with phosphatidylinositol 3-kinase. Int. Immunol. 6:769.

Ishida, Y., Y. Agata, K. Shibahara, T. Honjo. 1992. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11:3887.

Greenwald, R. J., Y. E. Latchman, A. H. Sharpe. 2002. Negative co-receptors on lymphocytes. Curr. Opin. Immunol. 14:391.

Okazaki, T., Y. Iwai, T. Honjo. 2002. New regulatory co-receptors: inducible co-stimulator and PD-1. Curr. Opin. Immunol. 14:779.

Bennett, F., D. Luxenberg, V. Ling, I. M. Wang, K. Marquette, D. Lowe, N. Khan, G. Veldman, K. A. Jacobs, V. E. Valge-Archer, et al 2003. Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses. J. Immunol. 170:711.

Okazaki, T., A. Maeda, H. Nishimura, T. Kurosaki, T. Honjo. 2001. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc. Natl. Acad. Sci. USA 98:13866.

Dong, H., G. Zhu, K. Tamada, L. Chen. 1999. B7–H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat. Med. 5:1365.

Tseng, S. Y., M. Otsuji, K. Gorski, X. Huang, J. E. Slansky, S. I. Pai, A. Shalabi, T. Shin, D. M. Pardoll, H. Tsuchiya. 2001. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J. Exp. Med. 193:839.

Tamura, H., H. Dong, G. Zhu, G. L. Sica, D. B. Flies, K. Tamada, L. Chen. 2001. B7–H1 costimulation preferentially enhances CD28-independent T-helper cell function. Blood 97:1809.

Nishimura, H., N. Minato, T. Nakano, T. Honjo. 1998. Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int. Immunol. 10:1563.

Nishimura, H., M. Nose, H. Hiai, N. Minato, T. Honjo. 1999. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141.

Nishimura, H., T. Okazaki, Y. Tanaka, K. Nakatani, M. Hara, A. Matsumori, S. Sasayama, A. Mizoguchi, H. Hiai, N. Minato, T. Honjo. 2001. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:319.

Shlapatska, L. M., S. V. Mikhalap, A. G. Berdova, O. M. Zelensky, T. J. Yun, K. E. Nichols, E. A. Clark, S. P. Sidorenko. 2001. 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.

Sidorenko, S. P., E. A. Clark. 2003. The dual-function CD150 receptor subfamily: the viral attraction. Nat. Immunol. 4:19.

Latchman, Y., C. R. Wood, T. Chernova, D. Chaudhary, M. Borde, I. Chernova, Y. Iwai, A. J. Long, J. A. Brown, R. Nunes, et al 2001. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2:261.

Shan, X., M. J. Czar, S. C. Bunnell, P. Liu, Y. Liu, P. L. Schwartzberg, R. L. Wange. 2000. Deficiency of PTEN in Jurkat T cells causes constitutive localization of Itk to the plasma membrane and hyperresponsiveness to CD3 stimulation. Mol. Cell. Biol. 20:6945.

Riley, J. L., P. J. Blair, J. T. Musser, R. Abe, K. Tezuka, T. Tsuji, C. H. June. 2001. ICOS costimulation requires IL-2 and can be prevented by CTLA-4 engagement. J. Immunol. 166:4943.

Hansen, J. A., P. J. Martin, R. C. Nowinski. 1980. Monoclonal-antibodies identifying a novel T-cell antigen and Ia antigens of human-lymphocytes. Immunogenetics 10:247.

Riley, J. L., K. Schlienger, P. J. Blair, B. Carreno, N. Craighead, D. Kim, R. G. Carroll, C. H. June. 2000. Modulation of susceptibility to HIV-1 infection by the cytotoxic T lymphocyte antigen 4 costimulatory molecule. J. Exp. Med. 191:1987.

Thomas, A. K., M. V. Maus, W. S. Shalaby, C. H. June, J. L. Riley. 2002. A cell-based artificial antigen-presenting cell coated with anti-CD3 and CD28 antibodies enables rapid expansion and long-term growth of CD4 T lymphocytes. Clin. Immunol. 105:259.

Parry, R. V., C. A. Rumbley, L. H. Vandenberghe, C. H. June, J. L. Riley. 2003. CD28 and inducible costimulatory protein Src homology 2 binding domains show distinct regulation of phosphatidylinositol 3-kinase, Bcl-xL, and IL-2 expression in primary human CD4 T lymphocytes. J. Immunol. 171:166.

Wang, J., M. F. Wilkinson. 2000. Site-directed mutagenesis of large (13-kb) plasmids in a single-PCR procedure. BioTechniques 29:976.

O’Doherty, U., W. J. Swiggard, M. H. Malim. 2000. Human immunodeficiency virus type 1 spinoculation enhances infection through virus binding. J. Virol. 74:10074.

Parry, R. V., K. Reif, G. Smith, D. M. Sansom, B. A. Hemmings, S. G. Ward. 1997. Ligation of the T cell co-stimulatory receptor CD28 activates the serine-threonine protein kinase protein kinase B. Eur. J. Immunol. 27:2495.

Frauwirth, K. A., J. L. Riley, M. H. Harris, R. V. Parry, J. C. Rathmell, D. R. Plas, R. L. Elstrom, C. H. June, C. B. Thompson. 2002. The CD28 signaling pathway regulates glucose metabolism. Immunity 16:769.

Lewis, J., L. J. Eiben, D. L. Nelson, J. I. Cohen, K. E. Nichols, H. D. Ochs, L. D. Notarangelo, C. S. Duckett. 2001. Distinct interactions of the X-linked lymphoproliferative syndrome gene product SAP with cytoplasmic domains of members of the CD2 receptor family. Clin. Immunol. 100:15.

Kane, L. P., A. Weiss. 2003. The PI-3 kinase/Akt pathway and T cell activation: pleiotropic pathways downstream of PIP3. Immunol. Rev. 192:7.

Riley, J. L., M. Mao, S. Kobayashi, M. Biery, J. Burchard, G. Cavet, B. P. Gregson, C. H. June, P. S. Linsley. 2002. Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proc. Natl. Acad. Sci. USA 99:11790.

Diehn, M., A. A. Alizadeh, O. J. Rando, C. L. Liu, K. Stankunas, D. Botstein, G. R. Crabtree, P. O. Brown. 2002. Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation. Proc. Natl. Acad. Sci. USA 99:11796.

Blair, P. J., J. L. Riley, B. L. Levine, K. P. Lee, N. Craighead, T. Francomano, S. J. Perfetto, G. S. Gray, B. M. Carreno, C. H. June. 1998. CTLA-4 ligation delivers a unique signal to resting human CD4 T cells that inhibits interleukin-2 secretion but allows Bcl-xL induction. J. Immunol. 160:12.

Boise, L. H., A. J. Minn, P. J. Noel, C. H. June, M. A. Accavitti, T. Lindsten, C. B. Thompson. 1995. CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-xL. Immunity 3:87.

Agata, Y., A. Kawasaki, H. Nishimura, Y. Ishida, T. Tsubata, H. Yagita, T. Honjo. 1996. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8:765.

Carter, L., L. A. Fouser, J. Jussif, L. Fitz, B. Deng, C. R. Wood, M. Collins, T. Honjo, G. J. Freeman, B. M. Carreno. 2002. PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2. Eur. J. Immunol. 32:634.

Sathish, J. G., K. G. Johnson, K. J. Fuller, F. G. LeRoy, L. Meyaard, M. J. Sims, R. J. Matthews. 2001. Constitutive association of SHP-1 with leukocyte-associated Ig-like receptor-1 in human T cells. J. Immunol. 166:1763.

Howie, D., M. Simarro, J. Sayos, M. Guirado, J. Sancho, C. Terhorst. 2002. Molecular dissection of the signaling and costimulatory functions of CD150 (SLAM): CD150/SAP binding and CD150-mediated costimulation. Blood 99:957.

Poy, F., M. B. Yaffe, J. Sayos, K. Saxena, M. Morra, J. Sumegi, L. C. Cantley, C. Terhorst, M. J. Eck. 1999. Crystal structures of the XLP protein SAP reveal a class of SH2 domains with extended, phosphotyrosine-independent sequence recognition. Mol. Cell 4:555.

Sayos, J., C. Wu, M. Morra, N. Wang, X. Zhang, D. Allen, S. van Schaik, L. Notarangelo, R. Geha, M. G. Roncarolo, et al 1998. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395:462.

Brown, J. A., D. M. Dorfman, F. R. Ma, E. L. Sullivan, O. Munoz, C. R. Wood, E. A. Greenfield, G. J. Freeman. 2003. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J. Immunol. 170:1257.

Rodig, N., T. Ryan, J. A. Allen, H. Pang, N. Grabie, T. Chernova, E. A. Greenfield, S. C. Liang, A. H. Sharpe, A. H. Lichtman, G. J. Freeman. 2003. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur. J. Immunol. 33:3117.

Tsushima, F., H. Iwai, N. Otsuki, M. Abe, S. Hirose, T. Yamazaki, H. Akiba, H. Yagita, Y. Takahashi, K. Omura, et al 2003. Preferential contribution of B7–H1 to programmed death-1-mediated regulation of hapten-specific allergic inflammatory responses. Eur. J. Immunol. 33:2773.

Shin, T., G. Kennedy, K. Gorski, H. Tsuchiya, H. Koseki, M. Azuma, H. Yagita, L. Chen, J. Powell, D. Pardoll, F. Housseau. 2003. Cooperative B7-1/2 (CD80/CD86) and B7-DC costimulation of CD4+ T cells independent of the PD-1 receptor. J. Exp. Med. 198:31.

Li, C., C. Iosef, C. Y. Jia, V. K. Han, S. S. Li. . 2003. Dual functional roles for the X-linked lymphoproliferative syndrome gene product SAP/SH2D1A in signaling through the signaling lymphocyte activation molecule (SLAM) family of immune receptors. J. Biol. Chem. 278:3852.

Sayos, J., M. Martin, A. Chen, M. Simarro, D. Howie, M. Morra, P. Engel, C. Terhorst. 2001. Cell surface receptors Ly-9 and CD84 recruit the X-linked lymphoproliferative disease gene product SAP. Blood 97:3867.

Bottino, C., M. Falco, S. Parolini, E. Marcenaro, R. Augugliaro, S. Sivori, E. Landi, R. Biassoni, L. D. Notarangelo, L. Moretta, A. Moretta. 2001. NTB-A a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked lymphoproliferative disease. J. Exp. Med. 194:235.

Matthews, R. J., D. B. Bowne, E. Flores, M. L. Thomas. 1992. Characterization of hematopoietic intracellular protein tyrosine phosphatases: description of a phosphatase containing an SH2 domain and another enriched in proline-, glutamic acid-, serine-, and threonine-rich sequences. Mol. Cell. Biol. 12:2396.

Law, C. L., S. P. Sidorenko, K. A. Chandran, Z. Zhao, S. H. Shen, E. H. Fischer, E. A. Clark. 1996. CD22 associates with protein tyrosine phosphatase 1C, Syk, and phospholipase C-γ(1) upon B cell activation. J. Exp. Med. 183:547.

Pani, G., K. D. Fischer, I. Mlinaric-Rascan, K. A. Siminovitch. 1996. Signaling capacity of the T cell antigen receptor is negatively regulated by the PTP1C tyrosine phosphatase. J. Exp. Med. 184:839.

Pani, G., M. Kozlowski, J. C. Cambier, G. B. Mills, K. A. Siminovitch. 1995. Identification of the tyrosine phosphatase PTP1C as a B cell antigen receptor-associated protein involved in the regulation of B cell signaling. J. Exp. Med. 181:2077.

Tang, T. L., R. M. Freeman, Jr, A. M. O’Reilly, B. G. Neel, S. Y. Sokol. 1995. The SH2-containing protein-tyrosine phosphatase SH-PTP2 is required upstream of MAP kinase for early Xenopus development. Cell 80:473.

Bennett, A. M., S. F. Hausdorff, A. M. O’Reilly, R. M. Freeman, B. G. Neel. 1996. Multiple requirements for SHPTP2 in epidermal growth factor-mediated cell cycle progression. Mol. Cell. Biol. 16:1189.

Lehmann, U., J. Schmitz, M. Weissenbach, R. M. Sobota, M. Hortner, K. Friederichs, I. Behrmann, W. Tsiaris, A. Sasaki, J. Schneider-Mergener, et al 2003. SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130. J. Biol. Chem. 278:661.

Thông tin
Thông tin xuất bản

Journal of Immunology

Tập 173 Số 2

945-954

Thông tin tác giả