Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150)

Journal of Immunology

Volumn 185, Issue 1, 2010, Pages 190-202

  Yusuf, Isharat ^a,c   Kageyama, Robin ^a   Monticelli, Laurel ^a   Johnston, Robert J ^a,b   DiToro, Daniel ^a   Hansen, Kyle ^a   Barnett, Burton ^a   Crotty, Shane ^a,b  

^a LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY   (United States)

^b UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

^c MedImmune ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

B LYMPHOCYTE INDUCED MATURATION PROTEIN 1; CD150 ANTIGEN; CD200 ANTIGEN; CD4 ANTIGEN; CHEMOKINE RECEPTOR CXCR5; EPITOPE; GAMMA INTERFERON; INTERLEUKIN 21; INTERLEUKIN 4; PROTEIN BCL 6; SIGNALING LYMPHOCYTE ACTIVATION MOLECULE ASSOCIATED PROTEIN; TRANSCRIPTION FACTOR C MAF; TRANSCRIPTION FACTOR GATA 3; TRANSCRIPTION FACTOR T BET; CELL SURFACE RECEPTOR; LEUKOCYTE ANTIGEN; SH2D1A PROTEIN, MOUSE; SIGNAL PEPTIDE;

ANIMAL CELL; ARTICLE; B LYMPHOCYTE; CD4+ T LYMPHOCYTE; CELL POLARITY; CONTROLLED STUDY; CYTOKINE PRODUCTION; GERMINAL CENTER; HELPER CELL; LYMPHOCYTE DIFFERENTIATION; MOUSE; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; T LYMPHOCYTE SUBPOPULATION; ANIMAL; BIOSYNTHESIS; C57BL MOUSE; CELL CULTURE; CELL DIFFERENTIATION; COCULTURE; CYTOLOGY; GENETICS; IMMUNOLOGY; IMMUNOPHENOTYPING; METABOLISM; MOUSE MUTANT; PATHOLOGY; PHYSIOLOGY; SIGNAL TRANSDUCTION; TRANSGENIC MOUSE;

ANIMALS; ANTIGENS, CD; B-LYMPHOCYTE SUBSETS; CELL DIFFERENTIATION; CELLS, CULTURED; COCULTURE TECHNIQUES; GERMINAL CENTER; IMMUNOPHENOTYPING; INTERLEUKIN-4; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; MICE, TRANSGENIC; RECEPTORS, CELL SURFACE; SIGNAL TRANSDUCTION; T-LYMPHOCYTES, HELPER-INDUCER;

EID: 77955280012     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.0903505     Document Type: Article

References (100)

1. Schoenberger, S. P., and S. Crotty. 2008. Immunologic memory. In Fundamental Immunology, 6th Ed., W. E. Paul, ed. Lippincott Williams & Wilkins, Philadelphia. p. 862-898.
2. McHeyzer-Williams, M. 2008. B Lymphocyte biology. In Fundamental Immunology, 6th Ed., W. E. Paul, ed. Lippincott Williams & Wilkins, Philadelphia. p. 289-311.
3. Amanna, I. J., M. K. Slifka, and S. Crotty. 2006. Immunity and immunological memory following smallpox vaccination. Immunol. Rev. 211: 320-337.
4. Radbruch, A., G. Muehlinghaus, E. O. Luger, A. Inamine, K. G. Smith, T. Dörner, and F. Hiepe. 2006. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat. Rev. Immunol. 6: 741-750.
5. Tangye, S. G., and D. M. Tarlinton. 2009. Memory B cells: effectors of long-lived immune responses. Eur. J. Immunol. 39: 2065-2075.
6. Crotty, S., R. J. Johnston, and S. P. Schoenberger. 2010. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat. Immunol. 11: 114-120.
7. King, C., S. G. Tangye, and C. R. Mackay. 2008. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu. Rev. Immunol. 26: 741-766.
8. Ansel, K. M., L. J. McHeyzer-Williams, V. N. Ngo, M. G. McHeyzer-Williams, and J. G. Cyster. 1999. In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J. Exp. Med. 190: 1123-1134.
9. Allen, C. D., T. Okada, H. L. Tang, and J. G. Cyster. 2007. Imaging of germinal center selection events during affinity maturation. Science 315: 528-531.
10. Haynes, N. M., C. D. Allen, R. Lesley, K. M. Ansel, N. Killeen, and J. G. Cyster. 2007. 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.
11. Johnston, R. J., A. C. Poholek, D. DiToro, I. Yusuf, D. Eto, B. Barnett, A. L. Dent, J. Craft, and S. Crotty. 2009. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325: 1006-1010.
12. Yu, D., S. Rao, L. M. Tsai, S. K. Lee, Y. He, E. L. Sutcliffe, M. Srivastava, M. A. Linterman, L. Zheng, N. Simpson, et al. 2009. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31: 457-468.
13. Nurieva, R. I., Y. Chung, G. J. Martinez, X. O. Yang, S. Tanaka, T. D. Matskevitch, Y. H. Wang, and C. Dong. 2009. Bcl6 mediates the development of T follicular helper cells. Science 325: 1001-1005.
14. Crotty, S., E. N. Kersh, J. Cannons, P. L. Schwartzberg, and R. Ahmed. 2003. SAP is required for generating long-term humoral immunity. Nature 421: 282-287.
15. Kamperschroer, C., J. P. Dibble, D. L. Meents, P. L. Schwartzberg, and S. L. Swain. 2006. SAP is required for Th cell function and for immunity to influenza. J. Immunol. 177: 5317-5327.
16. Cannons, J. L., L. J. Yu, D. Jankovic, S. Crotty, R. Horai, M. Kirby, S. Anderson, A. W. Cheever, A. Sher, and P. L. Schwartzberg. 2006. SAP regulates T cell-mediated help for humoral immunity by a mechanism distinct from cytokine regulation. J. Exp. Med. 203: 1551-1565.
17. Moyron-Quiroz, J. E., M. M. McCausland, R. Kageyama, A. Sette, and S. Crotty. 2009. The smallpox vaccine induces an early neutralizing IgM response. Vaccine 28: 140-147.
18. Chen, Q., J. L. Cannons, J. C. Paton, H. Akiba, P. L. Schwartzberg, and C. M. Snapper. 2008. A novel ICOS-independent, but CD28- and SAP-dependent, pathway of T cell-dependent, polysaccharide-specific humoral immunity in response to intact Streptococcus pneumoniae versus pneumococcal conjugate vaccine. J. Immunol. 181: 8258-8266.
19. Veillette, A., S. Zhang, X. Shi, Z. Dong, D. Davidson, and M.-C. Zhong. 2008. SAP expression in T cells, not in B cells, is required for humoral immunity. Proc. Natl. Acad. Sci. USA 105: 1273-1278.
20. Al-Alem, U., C. Li, N. Forey, F. Relouzat, M. C. Fondanèche, S. V. Tavtigian, Z. Q. Wang, S. Latour, and L. Yin. 2005. Impaired Ig class switch in mice deficient for the X-linked lymphoproliferative disease gene Sap. Blood 106: 2069-2075. (Pubitemid 41291721)
21. Nichols, K. E., J. Hom, S. Y. Gong, A. Ganguly, C. S. Ma, J. L. Cannons, S. G. Tangye, P. L. Schwartzberg, G. A. Koretzky, and P. L. Stein. 2005. Regulation of NKT cell development by SAP, the protein defective in XLP. Nat. Med. 11: 340-345.
22. Griewank, K., C. Borowski, S. Rietdijk, N. Wang, A. Julien, D. G. Wei, A. A. Mamchak, C. Terhorst, and A. Bendelac. 2007. Homotypic interactions mediated by Slamf1 and Slamf6 receptors control NKT cell lineage development. Immunity 27: 751-762.
23. Cannons, J. L., L. J. Yu, B. Hill, L. A. Mijares, D. Dombroski, K. E. Nichols, A. Antonellis, G. A. Koretzky, K. Gardner, and P. L. Schwartzberg. 2004. SAP regulates T(H)2 differentiation and PKC-theta-mediated activation of NF-kappaB1. Immunity 21: 693-706.
24. Davidson, D., X. Shi, S. Zhang, H. Wang, M. Nemer, N. Ono, S. Ohno, Y. Yanagi, and A. Veillette. 2004. Genetic evidence linking SAP, the X-linked lymphoproliferative gene product, to Src-related kinase FynT in T(H)2 cytokine regulation. Immunity 21: 707-717. (Pubitemid 39487892)
25. Wu, C., K. B. Nguyen, G. C. Pien, N. Wang, C. Gullo, D. Howie, M. R. Sosa, M. J. Edwards, P. Borrow, A. R. Satoskar, et al. 2001. SAP controls T cell responses to virus and terminal differentiation of TH2 cells. Nat. Immunol. 2: 410-414.
26. Dong, Z., M. E. Cruz-Munoz, M. C. Zhong, R. Chen, S. Latour, and A. Veillette. 2009. Essential function for SAP family adaptors in the surveillance of hematopoietic cells by natural killer cells. Nat. Immunol. 10: 973-980.
27. Ma, C. S., K. E. Nichols, and S. G. Tangye. 2007. Regulation of cellular and humoral immune responses by the SLAM and SAP families of molecules. Annu. Rev. Immunol. 25: 337-379.
28. Malbran, A., L. Belmonte, B. Ruibal-Ares, P. Baré, I. Massud, C. Parodi, M. Felippo, R. Hodinka, K. Haines, K. E. Nichols, and M. M. de Bracco. 2004. Loss of circulating CD27+ memory B cells and CCR4+ T cells occurring in association with elevated EBV loads in XLP patients surviving primary EBV infection. Blood 103: 1625-1631.
29. Ma, C. S., N. J. Hare, K. E. Nichols, L. Dupré, G. Andolfi, M.-G. Roncarolo, S. Adelstein, P. D. Hodgkin, and S. G. Tangye. 2005. Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells. J. Clin. Invest. 115: 1049-1059.
30. Ma, C. S., S. Pittaluga, D. T. Avery, N. J. Hare, I. Maric, A. D. Klion, K. E. Nichols, and S. G. Tangye. 2006. Selective generation of functional somatically mutated IgM+CD27+, but not Ig isotype-switched, memory B cells in X-linked lymphoproliferative disease. J. Clin. Invest. 116: 322-333.
31. Schwartzberg, P. L., K. L. Mueller, H. Qi, and J. L. Cannons. 2009. SLAM receptors and SAP influence lymphocyte interactions, development and function. Nat. Rev. Immunol. 9: 39-46.
32. Veillette, A. 2006. Immune regulation by SLAM family receptors and SAP-related adaptors. Nat. Rev. Immunol. 6: 56-66.
33. Chan, A. Y., J. M. Westcott, J. M. Mooney, E. K. Wakeland, and J. D. Schatzle. 2006. The role of SAP and the SLAM family in autoimmunity. Curr. Opin. Immunol. 18: 656-664.
34. Wandstrat, A. E., C. Nguyen, N. Limaye, A. Y. Chan, S. Subramanian, X. H. Tian, Y. S. Yim, A. Pertsemlidis, H. R. Garner, Jr., L. Morel, and E. K. Wakeland. 2004. Association of extensive polymorphisms in the SLAM/CD2 gene cluster with murine lupus. Immunity 21: 769-780.
35. Qi, H., J. L. Cannons, F. Klauschen, P. L. Schwartzberg, and R. N. Germain. 2008. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature 455: 764-769.
36. Czar, M. J., E. N. Kersh, L. A. Mijares, G. Lanier, J. Lewis, G. Yap, A. Chen, A. Sher, C. S. Duckett, R. Ahmed, and P. L. Schwartzberg. 2001. Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP. Proc. Natl. Acad. Sci. USA 98: 7449-7454.
37. Oxenius, A., M. F. Bachmann, R. M. Zinkernagel, and H. Hengartner. 1998. Virus-specific MHC-class II-restricted TCR-transgenic mice: effects on humoral and cellular immune responses after viral infection. Eur. J. Immunol. 28: 390-400.
38. Jennings, P., A. Chan, P. Schwartzberg, E. K. Wakeland, and D. Yuan. 2008. Antigen-specific responses and ANA production in B6.Sle1b mice: a role for SAP. J. Autoimmun. 31: 345-353.
39. McCausland, M. M., I. Yusuf, H. Tran, N. Ono, Y. Yanagi, and S. Crotty. 2007. SAP regulation of follicular helper CD4 T cell development and humoral immunity is independent of SLAM and Fyn kinase. J. Immunol. 178: 817-828.
40. Vinuesa, C. G., S. G. Tangye, B. Moser, and C. R. Mackay. 2005. Follicular B helper T cells in antibody responses and autoimmunity. Nat. Rev. Immunol. 5: 853-865.
41. McHeyzer-Williams, L. J., N. Pelletier, L. Mark, N. Fazilleau, and M. G. McHeyzer-Williams. 2009. Follicular helper T cells as cognate regulators of B cell immunity. Curr. Opin. Immunol. 21: 266-273.
42. Vinuesa, C. G., M. C. Cook, C. Angelucci, V. Athanasopoulos, L. Rui, K. M. Hill, D. Yu, H. Domaschenz, B. Whittle, T. Lambe, et al. 2005. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435: 452-458.
43. Nurieva, R. I., Y. Chung, D. Hwang, X. O. Yang, H. S. Kang, L. Ma, Y. H. Wang, S. S. Watowich, A. M. Jetten, Q. Tian, and C. Dong. 2008. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29: 138-149.
44. Akiba, H., K. Takeda, Y. Kojima, Y. Usui, N. Harada, T. Yamazaki, J. Ma, K. Tezuka, H. Yagita, and K. Okumura. 2005. The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo. J. Immunol. 175: 2340-2348.
45. Fazilleau, N., L. J. McHeyzer-Williams, H. Rosen, and M. G. McHeyzer-Williams. 2009. The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nat. Immunol. 10: 375-384.
46. Reinhardt, R. L., H. E. Liang, and R. M. Locksley. 2009. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat. Immunol. 10: 385-393.
47. Laszlo, G., K. S. Hathcock, H. B. Dickler, and R. J. Hodes. 1993. Characterization of a novel cell-surface molecule expressed on subpopulations of activated T and B cells. J. Immunol. 150: 5252-5262.
48. Naito, Y., H. Takematsu, S. Koyama, S. Miyake, H. Yamamoto, R. Fujinawa, M. Sugai, Y. Okuno, G. Tsujimoto, T. Yamaji, et al. 2007. Germinal center marker GL7 probes activation-dependent repression of N-glycolylneuraminic acid, a sialic acid species involved in the negative modulation of B-cell activation. Mol. Cell. Biol. 27: 3008-3022.
49. Duong, B. H., H. Tian, T. Ota, G. Completo, S. Han, J. L. Vela, M. Ota, M. Kubitz, N. Bovin, J. Paulson, and D. Nemazee. Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo. J Exp Med 207: 173-187.
50. Powell, L. D., and A. Varki. 1994. The oligosaccharide binding specificities of CD22 beta, a sialic acid-specific lectin of B cells. J. Biol. Chem. 269: 10628-10636.
51. Barber, D. L., E. J. Wherry, D. Masopust, B. Zhu, J. P. Allison, A. H. Sharpe, G. J. Freeman, and R. Ahmed. 2006. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439: 682-687.
52. King, I., and M. Mohrs. 2009. IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J. Exp. Med. 206: 1001-1007.
53. Zaretsky, A. G., J. J. Taylor, I. L. King, F. A. Marshall, M. Mohrs, and E. J. Pearce. 2009. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J. Exp. Med. 206: 991-999.
54. Brooks, D. G., L. Teyton, M. B. Oldstone, and D. B. McGavern. 2005. Intrinsic functional dysregulation of CD4 T cells occurs rapidly following persistent viral infection. J. Virol. 79: 10514-10527.
55. Elsaesser, H., K. Sauer, and D. G. Brooks. 2009. IL-21 is required to control chronic viral infection. Science 324: 1569-1572.
56. Yi, J. S., M. Du, and A. J. Zajac. 2009. A vital role for interleukin-21 in the control of a chronic viral infection. Science 324: 1572-1576.
57. Harrington, L. E., K. M. Janowski, J. R. Oliver, A. J. Zajac, and C. T. Weaver. 2008. Memory CD4 T cells emerge from effector T-cell progenitors. Nature 452: 356-360.
58. Ma, C. S., S. Suryani, D. T. Avery, A. Chan, R. Nanan, B. Santner-Nanan, E. K. Deenick, and S. G. Tangye. 2009. Early commitment of naïve human CD4(+) T cells to the T follicular helper (T(FH)) cell lineage is induced by IL-12. Immunol. Cell Biol. 87: 590-600.
59. Rasheed, A. U., H. P. Rahn, F. Sallusto, M. Lipp, and G. Müller. 2006. Follicular B helper T cell activity is confined to CXCR5(hi)ICOS(hi) CD4 T cells and is independent of CD57 expression. Eur. J. Immunol. 36: 1892-1903.
60. Chtanova, T., S. G. Tangye, R. Newton, N. Frank, M. R. Hodge, M. S. Rolph, and C. R. Mackay. 2004. 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.
61. Howie, D., S. Okamoto, S. Rietdijk, K. Clarke, N. Wang, C. Gullo, J. P. Bruggeman, S. Manning, A. J. Coyle, E. Greenfield, et al. 2002. The role of SAP in murine CD150 (SLAM)-mediated T-cell proliferation and interferon gamma production. Blood 100: 2899-2907.
62. Aversa, G., C. C. Chang, J. M. Carballido, B. G. Cocks, and J. E. de Vries. 1997. Engagement of the signaling lymphocytic activation molecule (SLAM) on activated T cells results in IL-2-independent, cyclosporin A-sensitive T cell proliferation and IFN-gamma production. J. Immunol. 158: 4036-4044. (Pubitemid 127483900)
63. Castro, A. G., T. M. Hauser, B. G. Cocks, J. Abrams, S. Zurawski, T. Churakova, F. Zonin, D. Robinson, S. G. Tangye, G. Aversa, et al. 1999. Molecular and functional characterization of mouse signaling lymphocytic activation molecule (SLAM): differential expression and responsiveness in Th1 and Th2 cells. J. Immunol. 163: 5860-5870.
64. Kumar, K. R., L. Li, M. Yan, M. Bhaskarabhatla, A. B. Mobley, C. Nguyen, J. M. Mooney, J. D. Schatzle, E. K. Wakeland, and C. Mohan. 2006. Regulation of B cell tolerance by the lupus susceptibility gene Ly108. Science 312: 1665-1669.
65. Veillette, A., M. E. Cruz-Munoz, and M. C. Zhong. 2006. SLAM family receptors and SAP-related adaptors: matters arising. Trends Immunol. 27: 228-234.
66. Yan, Q., V. N. Malashkevich, A. Fedorov, E. Fedorov, E. Cao, J. W. Lary, J. L. Cole, S. G. Nathenson, and S. C. Almo. 2007. Structure of CD84 provides insight into SLAM family function. Proc. Natl. Acad. Sci. USA 104: 10583-10588.
67. Cao, E., U. A. Ramagopal, A. Fedorov, E. Fedorov, Q. Yan, J. W. Lary, J. L. Cole, S. G. Nathenson, and S. C. Almo. 2006. NTB-A receptor crystal structure: insights into homophilic interactions in the signaling lymphocytic activation molecule receptor family. Immunity 25: 559-570.
68. Mavaddat, N., D. W. Mason, P. D. Atkinson, E. J. Evans, R. J. Gilbert, D. I. Stuart, J. A. Fennelly, A. N. Barclay, S. J. Davis, and M. H. Brown. 2000. Signaling lymphocytic activation molecule (CDw150) is homophilic but self-associates with very low affinity. J. Biol. Chem. 275: 28100-28109.
69. Nanda, N., P. Andre, M. Bao, K. Clauser, F. Deguzman, D. Howie, P. B. Conley, C. Terhorst, and D. R. Phillips. 2005. Platelet aggregation induces platelet aggregate stability via SLAM family receptor signaling. Blood 106: 3028-3034.
70. Cannons, J. L., H. Qi, K. T. Lu, M. Dutta, J. Gomez-Rodriguez, J. Cheng, E. K. Wakeland, R. N. Germain, and P. L. Schwartzberg. 2010. Optimal germinal center responses require a multistage T cell:B cell adhesion process involving integrins, SLAM-associated protein, and CD84. Immunity 32: 253-265.
71. Calpe, S., N. Wang, X. Romero, S. B. Berger, A. Lanyi, P. Engel, and C. Terhorst. 2008. The SLAM and SAP gene families control innate and adaptive immune responses. Adv. Immunol. 97: 177-250.
72. Graham, D. B., M. P. Bell, M. M. McCausland, C. J. Huntoon, J. van Deursen, W. A. Faubion, S. Crotty, and D. J. McKean. 2006. Ly9 (CD229)-deficient mice exhibit T cell defects yet do not share several phenotypic characteristics associated with SLAM- and SAP-deficient mice. J. Immunol. 176: 291-300.
73. Howie, D., F. S. Laroux, M. Morra, A. R. Satoskar, L. E. Rosas, W. A. Faubion, A. Julien, S. Rietdijk, A. J. Coyle, C. Fraser, and C. Terhorst. 2005. Cutting edge: the SLAM family receptor Ly108 controls T cell and neutrophil functions. J. Immunol. 174: 5931-5935.
74. Paul, W. E., and J. Ohara. 1987. B-cell stimulatory factor-1/interleukin 4. Annu. Rev. Immunol. 5: 429-459.
75. Kopf, M., G. Le Gros, A. J. Coyle, M. Kosco-Vilbois, and F. Brombacher. 1995. Immune responses of IL-4, IL-5, IL-6 deficient mice. Immunol. Rev. 148: 45-69.
76. Grusby, M. J. 1997. Stat4- and Stat6-deficient mice as models for manipulating T helper cell responses. Biochem. Soc. Trans. 25: 359-360.
77. Tsiagbe, V. K., and G. J. Thorbecke. 1998. Overview of germinal center function and structure in normal and genetically engineered mice. In The Biology of Germinal Centers in Lymphoid Tissue. G. J. Thorbecke, and V. K. Tisagbe, eds. Springer-Verlag Berlin Heidelberg, New York. p. 1-63.
78. Kaplan, M. H., U. Schindler, S. T. Smiley, and M. J. Grusby. 1996. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 4: 313-319.
79. Fazilleau, N., L. Mark, L. J. McHeyzer-Williams, and M. G. McHeyzer-Williams. 2009. Follicular helper T cells: lineage and location. Immunity 30: 324-335.
80. Ozaki, K., R. Spolski, C. G. Feng, C. F. Qi, J. Cheng, A. Sher, H. C. Morse, 3rd, C. Liu, P. L. Schwartzberg, and W. J. Leonard. 2002. A critical role for IL-21 in regulating immunoglobulin production. Science 298: 1630-1634.
81. Linterman, M. A., R. J. Rigby, R. K. Wong, D. Yu, R. Brink, J. L. Cannons, P. L. Schwartzberg, M. C. Cook, G. D. Walters, and C. G. Vinuesa. 2009. Follicular helper T cells are required for systemic autoimmunity. J. Exp. Med. 206: 561-576.
82. Zotos, D., J. M. Coquet, Y. Zhang, A. Light, K. D'Costa, A. Kallies, L. M. Corcoran, D. I. Godfrey, K.-M. Toellner, M. J. Smyth, et al. 2010. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J. Exp. Med. 207: 365-378.
83. Linterman, M. A., L. Beaton, D. Yu, R. R. Ramiscal, M. Srivastava, J. J. Hogan, N. K. Verma, M. J. Smyth, R. J. Rigby, and C. G. Vinuesa. 2010. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J. Exp. Med. 207: 353-363.
84. Poholek, A. C., K. Hansen, S. G. Hernandez, D. Eto, A. Chandele, J. S. Weinstein, X. Dong, J. M. Odegard, S. M. Kaech, A. L. Dent, S. Crotty and J. Craft. 2010. In vivo regulation of Bcl6 and T follicular helper cell development. J. Immunol. 185: 313-326.
85. Vogelzang, A., H. M. McGuire, D. Yu, J. Sprent, C. R. Mackay, and C. King. 2008. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29: 127-137.
86. Korn, T., E. Bettelli, W. Gao, A. Awasthi, A. Jäger, T. B. Strom, M. Oukka, and V. K. Kuchroo. 2007. IL-21 initiates an alternative pathway to induce proin- flammatory T(H)17 cells. Nature 448: 484-487.
87. Nelms, K., A. D. Keegan, J. Zamorano, J. J. Ryan, and W. E. Paul. 1999. The IL-4 receptor: signaling mechanisms and biologic functions. Annu. Rev. Immunol. 17: 701-738.
88. Wurster, A. L., V. L. Rodgers, M. F. White, T. L. Rothstein, and M. J. Grusby. 2002. Interleukin-4-mediated protection of primary B cells from apoptosis through Stat6-dependent up-regulation of Bcl-xL. J. Biol. Chem. 277: 27169-27175.
89. Dufort, F. J., B. F. Bleiman, M. R. Gumina, D. Blair, D. J. Wagner, M. F. Roberts, Y. Abu-Amer, and T. C. Chiles. 2007. Cutting edge: IL-4-mediated protection of primary B lymphocytes from apoptosis via Stat6-dependent regulation of glycolytic metabolism. J. Immunol. 179: 4953-4957.
90. Ettinger, R., S. Kuchen, and P. E. Lipsky. 2008. The role of IL-21 in regulating B-cell function in health and disease. Immunol. Rev. 223: 60-86.
91. Ettinger, R., G. P. Sims, A. M. Fairhurst, R. Robbins, Y. S. da Silva, R. Spolski, W. J. Leonard, and P. E. Lipsky. 2005. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J. Immunol. 175: 7867-7879.
92. Avery, D. T., V. L. Bryant, C. S. Ma, R. de Waal Malefyt, and S. G. Tangye. 2008. IL-21-induced isotype switching to IgG and IgA by human naive B cells is differentially regulated by IL-4. J. Immunol. 181: 1767-1779.
93. Bryant, V. L., C. S. Ma, D. T. Avery, Y. Li, K. L. Good, L. M. Corcoran, R. de Waal Malefyt, and S. G. Tangye. 2007. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5+ T follicular helper cells. J. Immunol. 179: 8180-8190.
94. Ozaki, K., R. Spolski, R. Ettinger, H. P. Kim, G. Wang, C. F. Qi, P. Hwu, D. J. Shaffer, S. Akilesh, D. C. Roopenian, et al. 2004. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J. Immunol. 173: 5361-5371.
95. Dienz, O., S. M. Eaton, J. P. Bond, W. Neveu, D. Moquin, R. Noubade, E. M. Briso, C. Charland, W. J. Leonard, G. Ciliberto, et al. 2009. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells. J. Exp. Med. 206: 69-78.
96. Wang, N., A. Satoskar, W. Faubion, D. Howie, S. Okamoto, S. Feske, C. Gullo, K. Clarke, M. R. Sosa, A. H. Sharpe, and C. Terhorst. 2004. The cell surface receptor SLAM controls T cell and macrophage functions. J. Exp. Med. 199: 1255-1264.
97. Li, W., M. H. Sofi, S. Rietdijk, N. Wang, C. Terhorst, and C. H. Chang. 2007. The SLAM-associated protein signaling pathway is required for development of CD4+ T cells selected by homotypic thymocyte interaction. Immunity 27: 763-774.
98. Wang, Z. Y., S. Kusam, V. Munugalavadla, R. Kapur, R. R. Brutkiewicz, and A. L. Dent. 2006. Regulation of Th2 cytokine expression in NKT cells: unconventional use of Stat6, GATA-3, and NFAT2. J. Immunol. 176: 880-888.
99. Zhu, J., J. Cote-Sierra, L. Guo, and W. E. Paul. 2003. Stat5 activation plays a critical role in Th2 differentiation. Immunity 19: 739-748.
100. Awasthi, A., and V. K. Kuchroo. 2009. Immunology. The yin and yang of follicular helper T cells. Science 325: 953-955.