Dynamics of B cells in germinal centres
Tóm tắt
Từ khóa
Tài liệu tham khảo
Jacob, J., Kelsoe, G., Rajewsky, K. & Weiss, U. Intraclonal generation of antibody mutants in germinal centres. Nature 354, 389–392 (1991).
Berek, C., Berger, A. & Apel, M. Maturation of the immune response in germinal centers. Cell 67, 1121–1129 (1991).
Blink, E. J. et al. Early appearance of germinal center-derived memory B cells and plasma cells in blood after primary immunization. J. Exp. Med. 201, 545–554 (2005).
Batista, F. D. & Harwood, N. E. The who, how and where of antigen presentation to B cells. Nature Rev. Immunol. 9, 15–27 (2009).
Okada, T. et al. Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. PLoS Biol. 3, e150 (2005).
Qi, H., Cannons, J. L., Klauschen, F., Schwartzberg, P. L. & Germain, R. N. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature 455, 764–769 (2008).
Jacob, J. & Kelsoe, G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl) acetyl. II. A common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers. J. Exp. Med. 176, 679–687 (1992).
Paus, D. et al. Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. J. Exp. Med. 203, 1081–1091 (2006).
O'Connor, B. P. et al. Imprinting the fate of antigen-reactive B cells through the affinity of the B cell receptor. J. Immunol. 177, 7723–7732 (2006).
Taylor, J. J., Pape, K. A. & Jenkins, M. K. A germinal center-independent pathway generates unswitched memory B cells early in the primary response. J. Exp. Med. 209, 597–606 (2012).
Dal Porto, J. M., Haberman, A. M., Kelsoe, G. & Shlomchik, M. J. Very low affinity B cells form germinal centers, become memory B cells, and participate in secondary immune responses when higher affinity competition is reduced. J. Exp. Med. 195, 1215–1221 (2002).
Shih, T. A., Meffre, E., Roederer, M. & Nussenzweig, M. C. Role of BCR affinity in T cell dependent antibody responses in vivo. Nature Immunol. 3, 570–575 (2002).
Schwickert, T. A. et al. A dynamic T cell-limited checkpoint regulates affinity-dependent B cell entry into the germinal center. J. Exp. Med. 208, 1243–1252 (2011).
Gatto, D., Paus, D., Basten, A., Mackay, C. R. & Brink, R. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses. Immunity 31, 259–269 (2009).
Pereira, J. P., Kelly, L. M., Xu, Y. & Cyster, J. G. EBI2 mediates B cell segregation between the outer and centre follicle. Nature 460, 1122–1126 (2009).
Kerfoot, S. M. et al. Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone. Immunity 34, 947–960 (2011).
Kitano, M. et al. Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. Immunity 34, 961–972 (2011).
Choi, Y. S. et al. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 34, 932–946 (2011).
Baumjohann, D., Okada, T. & Ansel, K. M. Cutting Edge: Distinct waves of BCL6 expression during T follicular helper cell development. J. Immunol. 187, 2089–2092 (2011). References 18–21 collectively show that antigen-activated B cells and T cells are committed to differentiate into GC B cells and T FH cells outside of the follicle.
Coffey, F., Alabyev, B. & Manser, T. Initial clonal expansion of germinal center B cells takes place at the perimeter of follicles. Immunity 30, 599–609 (2009).
Bannard, O. et al. Germinal center centroblasts transition to a centrocyte phenotype according to a timed program and depend on the dark zone for effective selection. Immunity 39, 912–924 (2013).
Allen, C. D., Okada, T., Tang, H. L. & Cyster, J. G. Imaging of germinal center selection events during affinity maturation. Science 315, 528–531 (2007).
Huang, C. et al. The BCL6 RD2 domain governs commitment of activated B cells to form germinal centers. Cell Rep. 8, 1497–1508 (2014).
Allen, C. D. et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nature Immunol. 5, 943–952 (2004).
Caron, G., Le Gallou, S., Lamy, T., Tarte, K. & Fest, T. CXCR4 expression functionally discriminates centroblasts versus centrocytes within human germinal center B cells. J. Immunol. 182, 7595–7602 (2009).
Green, J. A. et al. The sphingosine 1-phosphate receptor S1P2 maintains the homeostasis of germinal center B cells and promotes niche confinement. Nature Immunol. 12, 672–680 (2011).
Cinamon, G. et al. Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nature Immunol. 5, 713–720 (2004).
Cannons, J. L. et al. Optimal germinal center responses require a multistage T cell:B cell adhesion process involving integrins, SLAM-associated protein, and CD84. Immunity 32, 253–265 (2010).
Basso, K. & Dalla-Favera, R. Roles of BCL6 in normal and transformed germinal center B cells. Immunol. Rev. 247, 172–183 (2012).
Crotty, S., Johnston, R. J. & Schoenberger, S. P. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nature Immunol. 11, 114–120 (2010).
Khiem, D., Cyster, J. G., Schwarz, J. J. & Black, B. L. A p38 MAPK–MEF2C pathway regulates B-cell proliferation. Proc. Acad. Natl Sci. USA 105, 17067–17072 (2008).
Wilker, P. R. et al. Transcription factor Mef2c is required for B cell proliferation and survival after antigen receptor stimulation. Nature Immunol. 9, 603–612 (2008).
Ying, C. Y. et al. MEF2B mutations lead to deregulated expression of the oncogene BCL6 in diffuse large B cell lymphoma. Nature Immunol. 14, 1084–1092 (2013).
De Silva, N. S., Simonetti, G., Heise, N. & Klein, U. The diverse roles of IRF4 in late germinal center B-cell differentiation. Immunol. Rev. 247, 73–92 (2012).
Shaffer, A. L., Emre, N. C., Romesser, P. B. & Staudt, L. M. IRF4: Immunity. Malignancy! Therapy? Clin. Cancer Res. 15, 2954–2961 (2009).
Bollig, N. et al. Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation. Proc. Acad. Natl Sci. USA 109, 8664–8669 (2012).
Ochiai, K. et al. Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4. Immunity 38, 918–929 (2013).
Willis, S. N. et al. Transcription factor IRF4 regulates germinal center cell formation through a B cell-intrinsic mechanism. J. Immunol. 192, 3200–3206 (2014).
Saito, M. et al. A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell 12, 280–292 (2007).
Klein, U. et al. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nature Immunol. 7, 773–782 (2006).
Sciammas, R. et al. An incoherent regulatory network architecture that orchestrates B cell diversification in response to antigen signaling. Mol. Sys Biol. 7, 495 (2011).
Dominguez-Sola, D. et al. The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nature Immunol. 13, 1083–1091 (2012).
Klein, U. et al. Transcriptional analysis of the B cell germinal center reaction. Proc. Acad. Natl Sci. USA 100, 2639–2644 (2003).
Calado, D. P. et al. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nature Immunol. 13, 1092–1100 (2012). References 46 and 49 define the long unknown role of the MYC proto-oncogene in GC formation and in the maintenance of the GC reaction.
Peled, J. U. et al. Requirement for cyclin D3 in germinal center formation and function. Cell Res. 20, 631–646 (2010).
Cato, M. H., Chintalapati, S. K., Yau, I. W., Omori, S. A. & Rickert, R. C. Cyclin D3 is selectively required for proliferative expansion of germinal center B cells. Mol. Cell. Biol. 31, 127–137 (2011).
Hatzi, K. & Melnick, A. Breaking bad in the germinal center: how deregulation of BCL6 contributes to lymphomagenesis. Trends Mol. Med. 20, 343–352 (2014).
Vikstrom, I. et al. Mcl-1 is essential for germinal center formation and B cell memory. Science 330, 1095–1099 (2010). This study shows that MCL1 is the main anti-apoptotic regulator in GC B cells.
Gerondakis, S. & Siebenlist, U. Roles of the NF-κB pathway in lymphocyte development and function. Cold Spring Harb. Perspect. Biol. 2, a000182 (2010).
Jacque, E. et al. IKK-induced NF-êB1 p105 proteolysis is critical for B cell antibody responses to T cell-dependent antigen. J. Exp. Med. 211, 2085–2101 (2014).
Kim, U. et al. The B-cell-specific transcription coactivator OCA-B/OBF-1/Bob-1 is essential for normal production of immunoglobulin isotypes. Nature 383, 542–547 (1996).
Schubart, D. B., Rolink, A., Kosco-Vilbois, M. H., Botteri, F. & Matthias, P. B-cell-specific coactivator OBF-1/OCA-B/Bob1 required for immune response and germinal centre formation. Nature 383, 538–542 (1996).
Lee, C. H. et al. Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein. J. Exp. Med. 203, 63–72 (2006).
Kwon, K. et al. Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development. Immunity 28, 751–762 (2008).
Randall, K. L. et al. Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production. Nature Immunol. 10, 1283–1291 (2009).
Vilagos, B. et al. Essential role of EBF1 in the generation and function of distinct mature B cell types. J. Exp. Med. 209, 775–792 (2012).
Su, G. H. et al. Defective B cell receptor-mediated responses in mice lacking the Ets protein, Spi-B. EMBO J. 16, 7118–7129 (1997).
Muto, A. et al. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 429, 566–571 (2004).
Huang, C., Geng, H., Boss, I., Wang, L. & Melnick, A. Cooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation. Blood 123, 1012–1020 (2014).
Schwickert, T. A. et al. In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446, 83–87 (2007).
Hauser, A. E. et al. Definition of germinal-center B cell migration in vivo reveals predominant intrazonal circulation patterns. Immunity 26, 655–667 (2007).
Victora, G. D. et al. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143, 592–605 (2010). This study provides evidence that T cell help is the major factor promoting the selection of high-affinity antibodies in the light zone. Reference 24 and references 66–68 are an elegant series of studies that dissect the dynamics of GC B cell differentiation using intravital microscopy.
Allen, C. D., Okada, T. & Cyster, J. G. Germinal-center organization and cellular dynamics. Immunity 27, 190–202 (2007).
Hauser, A. E., Shlomchik, M. J. & Haberman, A. M. In vivo imaging studies shed light on germinal-centre development. Nature Rev. Immunol. 7, 499–504 (2007).
Victora, G. D. et al. Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas. Blood 120, 2240–2248 (2012).
Shulman, Z. et al. Dynamic signaling by T follicular helper cells during germinal center B cell selection. Science 345, 1058–1062 (2014).
Khalil, A. M., Cambier, J. C. & Shlomchik, M. J. B cell receptor signal transduction in the GC is short-circuited by high phosphatase activity. Science 336, 1178–1181 (2012). This work provides evidence that in GC B cells, BCR signalling is quiescent; rather, it seems that the role of the BCR is primarily to capture and to internalize antigen.
Gitlin, A. D., Shulman, Z. & Nussenzweig, M. C. Clonal selection in the germinal centre by regulated proliferation and hypermutation. Nature 509, 637–640 (2014). This study identifies the mechanism by which GC B cell clones with the highest affinity for the immunizing antigen are selectively expanded.
Di Noia, J. M. & Neuberger, M. S. Molecular mechanisms of antibody somatic hypermutation. Annu. Rev. Biochem. 76, 1–22 (2007).
Ramiscal, R. R. & Vinuesa, C. G. T-cell subsets in the germinal center. Immunol. Rev. 252, 146–155 (2013).
Liu, D. et al. T–B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction. Nature 517, 214–218 (2015). References 72 and 78 show that interactions between T FH cells and GC B cells are transient but extensive. These contacts initiate changes within T FH cells that guide the selection of high-affinity GC B cells.
Zhang, Y. et al. Germinal center B cells govern their own fate via antibody feedback. J. Exp. Med. 210, 457–464 (2013).
Shulman, Z. et al. T follicular helper cell dynamics in germinal centers. Science 341, 673–677 (2013).
Schwickert, T. A., Alabyev, B., Manser, T. & Nussenzweig, M. C. Germinal center reutilization by newly activated B cells. J. Exp. Med. 206, 2907–2914 (2009).
Chan, T. D. et al. Elimination of germinal-center-derived self-reactive B cells is governed by the location and concentration of self-antigen. Immunity 37, 893–904 (2012).
Klein, U. & Dalla-Favera, R. Germinal centres: role in B-cell physiology and malignancy. Nature Rev. Immunol. 8, 22–33 (2008).
Jacob, J., Przylepa, J., Miller, C. & Kelsoe, G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. III. The kinetics of V region mutation and selection in germinal center B cells. J. Exp. Med. 178, 1293–1307 (1993).
Basso, K. et al. Tracking CD40 signaling during germinal center development. Blood 104, 4088–4096 (2004).
Heise, N. et al. Germinal center B cell maintenance and differentiation are controlled by distinct NF-κB transcription factor subunits. J. Exp. Med. 211, 2103–2118 (2014).
Huntington, N. D. et al. CD45 links the B cell receptor with cell survival and is required for the persistence of germinal centers. Nature Immunol. 7, 190–198 (2006).
Goldberg, A. D., Allis, C. D. & Bernstein, E. Epigenetics: a landscape takes shape. Cell 128, 635–638 (2007).
Beguelin, W. et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23, 677–692 (2013).
Caganova, M. et al. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J. Clin. Invest. 123, 5009–5022 (2013). References 89 and 90 show an important role for epigenetic regulation in the maintenance of the dark zone B cell phenotype.
Raaphorst, F. M. et al. Cutting edge: polycomb gene expression patterns reflect distinct B cell differentiation stages in human germinal centers. J. Immunol. 164, 1–4 (2000).
Velichutina, I. et al. EZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis. Blood 116, 5247–5255 (2010).
Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).
Hatzi, K. et al. A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters. Cell Rep. 4, 578–588 (2013).
Xu, S., Guo, K., Zeng, Q., Huo, J. & Lam, K. P. The RNase III enzyme Dicer is essential for germinal center B-cell formation. Blood 119, 767–776 (2012).
Thai, T. H. et al. Regulation of the germinal center response by microRNA-155. Science 316, 604–608 (2007).
Vigorito, E. et al. microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity 27, 847–859 (2007).
Basso, K. et al. BCL6 positively regulates AID and germinal center gene expression via repression of miR-155. J. Exp. Med. 209, 2455–2465 (2012).
van den Berg, A. et al. High expression of B-cell receptor inducible gene BIC in all subtypes of Hodgkin lymphoma. Genes Chromosomes Cancer 37, 20–28 (2003).
Gururajan, M. et al. MicroRNA 125b inhibition of B cell differentiation in germinal centers. Int. Immunol. 22, 583–592 (2010).
de Yebenes, V. G. et al. miR-217 is an oncogene that enhances the germinal center reaction. Blood 124, 229–239 (2014).
Schneider, C. et al. MicroRNA 28 controls cell proliferation and is down-regulated in B-cell lymphomas. Proc. Acad. Natl Sci. USA 111, 8185–8190 (2014).
Feng, J. et al. IFN regulatory factor 8 restricts the size of the marginal zone and follicular B cell pools. J. Immunol. 186, 1458–1466 (2011).
Carotta, S. et al. The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation. J. Exp. Med. 211, 2169–2181 (2014).
McHeyzer-Williams, M., Okitsu, S., Wang, N. & McHeyzer-Williams, L. Molecular programming of B cell memory. Nature Rev. Immunol. 12, 24–34 (2012).
Zotos, D. & Tarlinton, D. M. Determining germinal centre B cell fate. Trends Immunol. 33, 281–288 (2012).
Shlomchik, M. J. & Weisel, F. Germinal center selection and the development of memory B and plasma cells. Immunol. Rev. 247, 52–63 (2012).
Nutt, S. L., Taubenheim, N., Hasbold, J., Corcoran, L. M. & Hodgkin, P. D. The genetic network controlling plasma cell differentiation. Semin. Immunol. 23, 341–349 (2011).
Barnett, B. E. et al. Asymmetric B cell division in the germinal center reaction. Science 335, 342–344 (2012).
Duffy, K. R. et al. Activation-induced B cell fates are selected by intracellular stochastic competition. Science 335, 338–341 (2012).
Meyer-Hermann, M. et al. A theory of germinal center B cell selection, division, and exit. Cell Rep. 2, 162–174 (2012).
Shaffer, A. L. 3rd, Young, R. M. & Staudt, L. M. Pathogenesis of human B cell lymphomas. Annu. Rev. Immunol. 30, 565–610 (2012).
Basso, K. & Dalla-Favera, R. Germinal centres and B cell lymphomagenesis. Nature Rev. Immunol. (in the press).
Sciammas, R. et al. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25, 225–236 (2006).
Shapiro-Shelef, M. et al. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19, 607–620 (2003).