Follicular helper T cells in immunity and systemic autoimmunity

Nature Reviews Rheumatology

Volumn 8, Issue 6, 2012, Pages 337-347

  Craft, Joseph E ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CD40 LIGAND; CHEMOKINE RECEPTOR CXCR5; INTERLEUKIN 12; PROTEIN BCL 6;

ANTIBODY PRODUCTION; AUTOIMMUNE DISEASE; B LYMPHOCYTE; CD4+ T LYMPHOCYTE; CYTOKINE RELEASE; DENDRITIC CELL; EFFECTOR CELL; FOLLICULAR HELPER T CELL; GERMINAL CENTER; HELPER CELL; HUMAN; HUMORAL IMMUNITY; IMMUNE RESPONSE; LUPUS ERYTHEMATOSUS NEPHRITIS; LYMPHOCYTE MIGRATION; NATURAL KILLER T CELL; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; SYSTEMIC LUPUS ERYTHEMATOSUS; T LYMPHOCYTE ACTIVATION; TH1 CELL; TH17 CELL; TH2 CELL;

ANIMALS; AUTOANTIBODIES; AUTOIMMUNITY; B-LYMPHOCYTES; CELL COMMUNICATION; DISEASE MODELS, ANIMAL; HUMANS; IMMUNITY; LUPUS ERYTHEMATOSUS, SYSTEMIC; LYMPH NODES; MICE; T-LYMPHOCYTES, HELPER-INDUCER;

EID: 84861694711     PISSN: 17594790     EISSN: 17594804     Source Type: Journal    
DOI: 10.1038/nrrheum.2012.58     Document Type: Review

References (137)

1. Campbell, D. J., Kim, C. H. & Butcher, E. C. Separable effector T cell populations specialized for B cell help or tissue inflammation. Nat. Immunol. 2, 876-881 (2001).
2. Murphy, K. M. & Reiner, S. L. The lineage decisions of helper T cells. Nat. Rev. Immunol. 2, 933-944 (2002). (Pubitemid 37323214)
3. Szabo, S. J. et al. A novel transcription factor, Tbet, directs TH1 lineage commitment. Cell 100, 655-669 (2000).
4. Zheng, W. & Flavell, R. A. The transcription factor GATA3 is necessary and sufficient for TH2 cytokine gene expression in CD4 T cells. Cell 89, 587-596 (1997). (Pubitemid 27511769)
5. Dang, E. V. et al. Control of T(H)17/T(REG) balance by hypoxia-inducible factor 1. Cell 146, 772-784 (2011).
6. Ivanov, I. I. et al. The orphan nuclear receptor ROR?t directs the differentiation program of proinflammatory IL17+ T Helper Cells. Cell 126, 1121-1133 (2006). (Pubitemid 44380299)
7. Yang, X. O. et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR? and ROR?. Immunity 28, 29-39 (2008).
8. Liang, S. C. et al. Interleukin (IL)22 and IL17 are coexpressed by TH17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271-2279 (2006). (Pubitemid 44498362)
9. Eyerich, S. et al. TH22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J. Clin. Invest. 119, 3573-3585 (2009).
10. Langrish, C. L. et al. IL23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233-240 (2005). (Pubitemid 40189432)
11. Koenders, M. I. et al. Blocking of interleukin17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin1. Am. J. Pathol. 167, 141-149 (2005). (Pubitemid 40884777)
12. Crispín, J. C. & Tsokos, G. C. Interleukin17producing T cells in lupus. Curr. Opin. Rheum. 22, 499-503 (2010).
13. Parker, D. C. T cell-dependent B cell activation. Annu. Rev. Immunol. 11, 331-360 (1993). (Pubitemid 23115011)
14. Liu, Y. J., Zhang, J., Lane, P. J., Chan, E. Y. & MacLennan, I. C. Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens. Eur. J. Immunol. 21, 2951-2962 (1991).
15. MacLennan, I. C. et al. Extrafollicular antibody responses. Immunol. Rev. 194, 8-18 (2003). (Pubitemid 36886424)
16. Jacob, J., Kassir, R. & Kelsoe, G. In situ studies of the primary immune response to (4hydroxy3-nitrophenyl)acetyl. I. The architecture and dynamics of responding cell populations. J. Exp. Med. 173, 1165-1175 (1991).
17. Berek, C., Berger, A. & Apel, M. Maturation of the immune response in germinal centers. Cell 67, 1121-1129 (1991). (Pubitemid 121001525)
18. 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).
19. 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).
20. 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).
21. Willimann, K. et al. The chemokine SLC is expressed in T cell areas of lymph nodes and mucosal lymphoid tissues and attracts activated T cells via CCR7. Eur. J. Immunol. 28, 2025-2034 (1998). (Pubitemid 28271719)
22. Nagira, M. et al. A lymphocyte-specific CC chemokine, secondary lymphoid tissue chemokine (SLC), is a highly efficient chemoattractant for B cells and activated T cells. Eur. J. Immunol. 28, 1516-1523 (1998). (Pubitemid 28221154)
23. Luther, S. A. et al. Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J. Immunol. 169, 424-433 (2002). (Pubitemid 34686164)
24. Haynes, N. M. et al. Role of CXCR5 and CCR7 in follicular TH cell positioning and appearance of a programmed cell death gene-1High germinal center-associated subpopulation. J. Immunol. 179, 5099-5108 (2007).
25. Poholek, A. C. et al. In vivo regulation of Bcl6 and T follicular helper cell development. J. Immunol. 185, 313-326 (2010).
26. Veerman, K. M. et al. Interaction of the selectin ligand PSGL1 with chemokines CCL21 and CCL19 facilitates efficient homing of T cells to secondary lymphoid organs. Nat. Immunol. 8, 532-539 (2007). (Pubitemid 46605921)
27. Ansel, K. M., McHeyzer-Williams, L. J., Ngo, V. N., McHeyzer-Williams, M. G. & Cyster, J. G. In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J. Exp. Med. 190, 1123-1134 (1999). (Pubitemid 29496505)
28. Walker, L. S. et al. Compromised OX40 function in CD28-deficient mice is linked with failure to develop CXC chemokine receptor 5positive CD4 cells and germinal centers. J. Exp. Med. 190, 1115-1122 (1999). (Pubitemid 29496504)
29. Gunn, M. D. et al. A Bcellhoming chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor1. Nature 391, 799-803 (1998). (Pubitemid 28099679)
30. Hardtke, S., Ohl, L. & Forster, R. Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient Bcell help. Blood 106, 1924-1931 (2005). (Pubitemid 41291702)
31. Akiba, H. et al. The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo. J. Immunol. 175, 2340-2348 (2005). (Pubitemid 41113843)
32. Nurieva, R. I. et al. Generation of T follicular helper cells is mediated by interleukin21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29, 138-149 (2008).
33. Johnston, R. J. et al. Bcl6 and Blimp1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006-1010 (2009).
34. 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).
35. Dong, C., Temann, U. A. & Flavell, R. A. Cutting edge: critical role of inducible costimulator in germinal center reactions. J. Immunol. 166, 3659-3662 (2001). (Pubitemid 32224886)
36. Odegard, J. M. et al. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL21 in systemic autoimmunity. J. Exp. Med. 205, 2873-2886 (2008).
37. Bossaller, L. et al. ICOS deficiency is associated with a severe reduction of CXCR5+ CD4 germinal center TH cells. J. Immunol. 177, 4927-4932 (2006). (Pubitemid 44469829)
38. Burmeister, Y. et al. ICOS controls the pool size of effector-memory and regulatory T cells. J. Immunol. 180, 774-782 (2008).
39. Good-Jacobson, K. L. et al. PD1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat. Immunol. 11, 535-542 (2010).
40. Reif, K. et al. Balanced responsiveness to chemoattractants from adjacent zones determines Bcell position. Nature 416, 94-99 (2002). (Pubitemid 34215407)
41. Hannedouche, S. et al. Oxysterols direct immune cell migration via EBI2. Nature 475, 524-527 (2011).
42. Liu, C. et al. Oxysterols direct Bcell migration through EBI2. Nature 475, 519-523 (2011).
43. 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).
44. 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).
45. Crotty, S., Kersh, E. N., Cannons, J., Schwartzberg, P. L. & Ahmed, R. SAP is required for generating long-term humoral immunity. Nature 421, 282-287 (2003). (Pubitemid 36139134)
46. Cannons, J. L. et al. SAP regulates T cell-mediated help for humoral immunity by a mechanism distinct from cytokine regulation. J. Exp. Med. 203, 1551-1565 (2006). (Pubitemid 43877615)
47. Qi, H., Cannons, J. L., Klauschen, F., Schwartzberg, P. L. & Germain, R. N. SAP-controlled TB cell interactions underlie germinal centre formation. Nature 455, 764-769 (2008).
48. Cunningham, A. F., Serre, K., Mohr, E., Khan, M. & Toellner, K. M. Loss of CD154 impairs the TH2 extrafollicular plasma cell response but not early T cell proliferation and interleukin4 induction. Immunology 113, 187-193 (2004). (Pubitemid 39312446)
49. Deenick, E. K. et al. Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling. Immunity 33, 241-253, (2010).
50. Schaerli, P., Loetscher, P. & Moser, B. Cutting edge: induction of follicular homing precedes effector TH cell development. J. Immunol. 167, 6082-6086 (2001). (Pubitemid 33081532)
51. Springer, T. A. Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu. Rev. Physiol. 57, 827-872 (1995).
52. Austrup, F. et al. P and Eselectin mediate recruitment of Thelper1 but not Thelper2 cells into inflammed tissues. Nature 385, 81-83 (1997). (Pubitemid 27024558)
53. Ley, K. & Kansas, G. S. Selectins in Tcell recruitment to non-lymphoid tissues and sites of inflammation. Nat. Rev. Immunol. 4, 325-335 (2004). (Pubitemid 38649275)
54. Kim, C. H. et al. Rules of chemokine receptor association with T cell polarization in vivo. J. Clin. Invest. 108, 1331-1339 (2001). (Pubitemid 33107761)
55. Dent, A. L., Shaffer, A. L., Yu, X., Allman, D. & Staudt, L. M. Control of inflammation, cytokine expression, and germinal center formation by BCL6. Science 276, 589-592 (1997). (Pubitemid 27193682)
56. Ye, B. H. et al. The BCL6 proto-oncogene controls germinal-centre formation and TH2-type inflammation. Nat. Genet. 16, 161-170 (1997).
57. Chtanova, T. et al. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-TH1/TH2 effector cells that provide help for B cells. J. Immunol. 173, 68-78 (2004). (Pubitemid 38797327)
58. Nurieva, R. I. et al. Bcl6 mediates the development of T follicular helper cells. Science 325, 1001-1005 (2009).
59. Yu, D. et al. The transcriptional repressor Bcl6 directs T follicular helper cell lineage commitment. Immunity 31, 457-468 (2009).
60. Johnston, R. J., Choi, Y. S., Diamond, J. A., Yang, J. A. & Crotty, S. STAT5 is a potent negative regulator of TFH cell differentiation. J. Exp. Med. http://dx.doi.org/10.1084/jem.20111174.
61. 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).
62. Garside, P. et al. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281, 96-99 (1998). (Pubitemid 28354051)
63. Breitfeld, D. et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192, 1545-1552 (2000).
64. Schaerli, P. et al. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192, 1553-1562 (2000).
65. Kim, C. H. et al. Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells. J. Exp. Med. 193, 1373-1381 (2001). (Pubitemid 32565966)
66. Jacob, J., Kelsoe, G., Rajewsky, K. & Weiss, U. Intraclonal generation of antibody mutants in germinal centres. Nature 354, 389-392 (1991). (Pubitemid 21896846)
67. Liu, Y. J. et al. Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. Immunity 4, 241-250 (1996). (Pubitemid 26131007)
68. Parrish-Novak, J. et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408, 57-63 (2000).
69. Mehta, D. S. et al. IL21 induces the apoptosis of resting and activated primary B cells. J. Immunol. 170, 4111-4118 (2003). (Pubitemid 36428174)
70. Jin, H., Carrio, R., Yu, A. & Malek, T. R. Distinct activation signals determine whether IL21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis. J. Immunol. 173, 657-665 (2004). (Pubitemid 38797396)
71. Ozaki, K. et al. Regulation of B cell differentiation and plasma cell generation by IL21, a novel inducer of Blimp1 and Bcl6. J. Immunol. 173, 5361-5371 (2004). (Pubitemid 39392119)
72. Ettinger, R. et al. IL21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J. Immunol. 175, 7867-7879 (2005). (Pubitemid 41798347)
73. Kuchen, S. et al. Essential role of IL21 in B cell activation, expansion, and plasma cell generation during CD4+ T cellB cell collaboration. J. Immunol. 179, 5886-5896 (2007).
74. Linterman, M.A. et al. IL21 acts directly on B cells to regulate Bcl6 expression and germinal center responses. J. Exp. Med. 207, 353-363 (2010).
75. Zotos, D. et al. IL21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J. Exp. Med. 207, 365-378 (2010).
76. Eto, D. et al. IL21 and IL6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (TFH) differentiation. PLoS One 6, e17739 (2011).
77. Ozaki, K. et al. A critical role for IL21 in regulating immunoglobulin production. Science 298, 1630-1634 (2002). (Pubitemid 35387203)
78. Hsu, H. C. et al. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat. Immunol. 9, 166-175 (2008).
79. Reinhardt, R. L., Liang, H. E. & Locksley, R. M. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat. Immunol. 10, 385-393 (2009).
80. King, I. L. & Mohrs, M. IL4producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J. Exp. Med. 206, 1001-1007 (2009).
81. Bauquet, A. T. et al. The costimulatory molecule ICOS regulates the expression of cMaf and IL21 in the development of follicular T helper cells and TH17 cells. Nat. Immunol. 10, 167-175 (2009).
82. Hams, E. et al. Blockade of B7H1 (programmed death ligand 1) enhances humoral immunity by positively regulating the generation of T follicular helper cells. J. Immunol. 186, 5648-5655 (2011).
83. Mempel, T. R., Henrickson, S. E. & Von Andrian, U. H. Tcell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427, 154-159 (2004). (Pubitemid 38094955)
84. Callard, R. E., Armitage, R. J., Fanslow, W. C. & Spriggs, M. K. CD40 ligand and its role in Xlinked hyper-IgM syndrome. Immunol. Today 14, 559-564 (1993). (Pubitemid 23316716)
85. Xu, J. et al. Mice deficient for the CD40 ligand. Immunity 1, 423-431 (1994).
86. McAdam, A. J. et al. ICOS is critical for CD40-mediated antibody class switching. Nature 409, 102-105 (2001). (Pubitemid 32098633)
87. Lee, S. K. et al. B cell priming for extrafollicular antibody responses requires Bcl6 expression by T cells. J. Exp. Med. 208, 1377-1388 (2011).
88. Barral, P. et al. B cell receptor-mediated uptake of CD1d-restricted antigen augments antibody responses by recruiting invariant NKT cell help in vivo. Proc. Natl Acad. Sci. USA 105, 8345-8350 (2008). (Pubitemid 351904758)
89. Leadbetter, E. A. et al. NK T cells provide lipid antigen-specific cognate help for B cells. Proc. Natl Acad. Sci. USA 105, 8339-8344 (2008). (Pubitemid 351904757)
90. King, I. L. et al. Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL21dependent manner. Nat. Immunol. 13, 44-50, (2011).
91. Chang, P. P. et al. Identification of Bcl6dependent follicular helper NKT cells that provide cognate help for B cell responses. Nat. Immunol. 13, 35-43 (2011).
92. Vinuesa, C. G., Sanz, I. & Cook, M. C. Dysregulation of germinal centres in autoimmune disease. Nat. Rev. Immunol. 9, 845-857 (2009).
93. Linterman, M.A. et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 17, 975-982 (2011).
94. Wollenberg, I. et al. Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. J. Immunol. 187, 4553-4560 (2011).
95. Chung, Y. et al. Follicular regulatory T cells expressing Foxp3 and Bcl6 suppress germinal center reactions. Nat. Med. 17, 983-988 (2011).
96. Alexander, C. M. et al. T regulatory cells participate in the control of germinal centre reactions. Immunology 133, 452-468 (2011).
97. Jang, E. et al. Foxp3+ regulatory T cells control humoral autoimmunity by suppressing the development of long-lived plasma cells. J. Immunol. 186, 1546-1553 (2011).
98. Ritchie, A. W., James, K. & Micklem, H. S. The distribution and possible significance of cells identified in human lymphoid tissue by the monoclonal antibody HNK1. Clin. Exp. Immunol. 51, 439-447 (1983). (Pubitemid 13144116)
99. Banerjee, D. & Thibert, R. F. Natural killer-like cells found in Bcell compartments of human lymphoid tissues. Nature 304, 270-272 (1983). (Pubitemid 13067102)
100. Kim, J. R., Lim, H. W., Kang, S. G., Hillsamer, P. & Kim, C. H. Human CD57+ germinal centerT cells are the major helpers for GCB cells and induce class switch recombination. BMC Immunol. 6, 3 (2005).
101. Casamayor-Palleja, M., Khan, M. & MacLennan, I. C. A subset of CD4+ memory T cells contains preformed CD40 ligand that is rapidly but transiently expressed on their surface after activation through the T cell receptor complex. J. Exp. Med. 181, 1293-1301 (1995).
102. Rasheed, A. U., Rahn, H. P., Sallusto, F., Lipp, M. & Müller, G. Follicular B helper T cell activity is confined to CXCR5hiICOShi CD4 T cells and is independent of CD57 expression. Eur. J. Immunol. 36, 1892-1903 (2006). (Pubitemid 44089055)
103. Lim, H. W. & Kim, C. H. Loss of IL7 receptor ? on CD4+ T cells defines terminally differentiated B cell-helping effector T cells in a B cell-rich lymphoid tissue. J. Immunol. 179, 7448-7456 (2007).
104. Chevalier, N. et al. CXCR5 expressing human central memory CD4 T cells and their relevance for humoral immune responses. J. Immunol. 186, 5556-5568 (2011).
105. Morita, R. et al. Human blood CXCR5+CD4+ T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34, 108-121 (2011).
106. MacLeod, M. K. et al. Memory CD4 T cells that express CXCR5 provide accelerated help to B cells. J. Immunol. 186, 2889-2896 (2011).
107. Bentebibel, S. E., Schmitt, N., Banchereau, J. & Ueno, H. Human tonsil Bcell lymphoma 6 (BCL6)-expressing CD4+ Tcell subset specialized for Bcell help outside germinal centers. Proc. Natl Acad. Sci. USA 108, E488-E497 (2011).
108. Dogan, I. et al. Multiple layers of B cell memory with different effector functions. Nat. Immunol. 10, 1292-1299 (2009).
109. Pepper, M., Pagán, A. J., Igyártó, B. Z., Taylor, J. J. & Jenkins, M. K. Opposing signals from the Bcl6 transcription factor and the interleukin2 receptor generate T helper 1 central and effector memory cells. Immunity 35, 583-595 (2011).
110. Marshall, H. D. et al. Differential expression of Ly6C and Tbet distinguish effector and memory TH1 CD4+ cell properties during viral infection. Immunity 35, 633-646 (2011).
111. Simpson, N. et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum. 62, 234-244 (2010).
112. Vinuesa, C. G. et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435, 452-458 (2005). (Pubitemid 40734237)
113. Luzina, I. G. et al. Spontaneous formation of germinal centers in autoimmune mice. J. Leukoc. Biol. 70, 578-584 (2001). (Pubitemid 32954768)
114. Linterman, M.A. et al. Follicular helper T cells are required for systemic autoimmunity. J. Exp. Med. 206, 561-576 (2009).
115. Bertossi, A. et al. Loss of Roquin induces early death and immune deregulation but not autoimmunity. J. Exp. Med. 208, 1749-1756 (2011).
116. Pisitkun, P. et al. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312, 1669-1672 (2006). (Pubitemid 43902669)
117. Bubier, J. A. et al. A critical role for IL21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proc. Natl Acad. Sci. USA 106, 1518-1523 (2009).
118. Herber, D. et al. IL21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL21R.Fc reduces disease progression. J. Immunol. 178, 3822-3830 (2007). (Pubitemid 46417651)
119. Peng, S. L., Moslehi, J. & Craft, J. Roles of interferon? and interleukin4 in murine lupus. J. Clin. Invest. 99, 1936-1946 (1997). (Pubitemid 27175941)
120. Masutani, K. et al. Predominance of TH1 immune response in diffuse proliferative lupus nephritis. Arthritis Rheum. 44, 2097-2106 (2001). (Pubitemid 33644053)
121. Mohan, C., Shi, Y., Laman, J. D. & Datta, S. K. Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J. Immunol. 154, 1470-1480 (1995).
122. Ma, J. et al. Autoimmune lpr/lpr mice deficient in CD40 ligand: spontaneous Ig class switching with dichotomy of autoantibody responses. J. Immunol. 157, 417-426 (1996). (Pubitemid 26190576)
123. Daikh, D. I., Finck, B. K., Linsley, P. S., Hollenbaugh, D. & Wofsy, D. Long-term inhibition of murine lupus by brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways. J. Immunol. 159, 3104-3108 (1997). (Pubitemid 127482065)
124. Grammer, A. C. et al. Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions. J. Clin. Invest. 112, 1506-1520 (2003). (Pubitemid 38056277)
125. Duffau, P. et al. Platelet CD154 potentiates interferon? secretion by plasmacytoid dendritic cells in systemic lupus erythematosus. Sci. Transl. Med. 2, 47ra63 (2010).
126. Peters, A. L., Stunz, L. L. & Bishop, G. A. CD40 and autoimmunity: the dark side of a great activator. Semin. Immunol. 21, 293-300 (2009).
127. Iwai, H. et al. Involvement of inducible costimulatorB7 homologous protein costimulatory pathway in murine lupus nephritis. J. Immunol. 171, 2848-2854 (2003). (Pubitemid 37093504)
128. William, J., Euler, C., Christensen, S. & Shlomchik, M. J. Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science 297, 2066-2070 (2002).
129. Hoyer, B. F. et al. Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J. Exp. Med. 199, 1577-1584 (2004). (Pubitemid 38780412)
130. Rankin, A. L. et al. IL21 receptor is required for the systemic accumulation of activated B and T lymphocytes in MRL/MpJ-Faslpr/lpr/J mice. J. Immunol. http://dx.doi.org/10.4049/jimmunol.1003871.
131. Hargreaves, D. C. et al. A coordinated change in chemokine responsiveness guides plasma cell movements. J. Exp. Med. 194, 45-56 (2001). (Pubitemid 32660436)
132. Cappione, A. 3rd. et al. Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus. J. Clin. Invest. 115, 3205-3216 (2005).
133. Yang, J. H. et al. Expression and function of inducible costimulator on peripheral blood T cells in patients with systemic lupus erythematosus. Rheumatology (Oxford) 44, 1245-1254 (2005).
134. Chang, A. et al. In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J. Immunol. 186, 1849-1860 (2011).
135. Weyand, C. M., Kang, Y. M., Kurtin, P. J. & Goronzy, J. J. The power of the third dimension: tissue architecture and autoimmunity in rheumatoid arthritis. Curr. Opin. Rheumatol. 15, 259-266 (2003). (Pubitemid 36534486)
136. Cantaert, T. et al. B lymphocyte autoimmunity in rheumatoid synovitis is independent of ectopic lymphoid neogenesis. J. Immunol. 181, 785-794 (2008).
137. Victoratos, P. & Kollias, G. Induction of autoantibody-mediated spontaneous arthritis critically depends on follicular dendritic cells. Immunity 30, 130-142 (2009).