Current understanding of Th2 cell differentiation and function

Abstract

Helper T cell (Th) has been identified as a critical immune cell for regulating immune response since 1980s. The type 2 helper T cell (Th2), characterized by the production of interleukin-4 (IL-4), IL-5 and IL-13, plays a critical role in immune response against helminths invading cutaneous or mucosal sites. It also has a functional role in the pathophysiology of allergic diseases such as asthma and allergic diarrhea. Currently, most studies have shed light on Th2 cell function and behavior in specific diseases, such as asthma and helminthes inflammation, but not on Th2 cell itself and its differentiation. Based on different cytokines and specific behavior in recent research, Th2 cell is also regarded as new subtypes of T cell, such as IL-9 secreting T cell (Th9) and CXCR5⁺ T follicular helper cells. Here, we will discuss the latest view of Th2 cell towards their function and the involvement of Th2 cell in diseases.

Keywords

type 2 helper T cell (Th2) / asthma / IL-9 secreting T cell (Th9) / T follicular helper cell

References

[1] Abbas, A.K., Murphy, K.M., and Sher, A. (1996). Functional diversity of helper T lymphocytes. Nature 383, 787-793 .8893001
[2] Agarwal, S., Avni, O., and Rao, A. (2000). Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo. Immunity 12, 643-652 .10894164
[3] Agarwal, S., and Rao, A. (1998). Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 9, 765-775 .9881967
[4] Allen, C.D., Okada, T., and Cyster, J.G. (2007). Germinal-center organization and cellular dynamics. Immunity 27, 190-202 .17723214
[5] Amsen, D., Antov, A., Jankovic, D., Sher, A., Radtke, F., Souabni, A., Busslinger, M., McCright, B., Gridley, T., and Flavell, R.A. (2007). Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity 27, 89-99 .17658279
[6] Amsen, D., Blander, J.M., Lee, G.R., Tanigaki, K., Honjo, T., and Flavell, R.A. (2004). Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117, 515-526 .15137944
[7] Angkasekwinai, P., Chang, S.H., Thapa, M., Watarai, H., and Dong, C. (2010). Regulation of IL-9 expression by IL-25 signaling. Nat Immunol 11, 250-256 .20154671
[8] Ansel, K.M., McHeyzer-Williams, L.J., Ngo, V.N., McHeyzer-Williams, M.G., and Cyster, J.G. (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 .10523610
[9] Barolo, S., Walker, R.G., Polyanovsky, A.D., Freschi, G., Keil, T., and Posakony, J.W. (2000). A notch-independent activity of suppressor of hairless is required for normal mechanoreceptor physiology. Cell 103, 957-969 .11136980
[10] Beriou, G., Bradshaw, E.M., Lozano, E., Costantino, C.M., Hastings, W.D., Orban, T., Elyaman, W., Khoury, S.J., Kuchroo, V.K., Baecher-Allan, C., (2010). TGF-beta induces IL-9 production from human Th17 cells. J Immunol 185, 46-54 .20498357
[11] Bird, J.J., Brown, D.R., Mullen, A.C., Moskowitz, N.H., Mahowald, M.A., Sider, J.R., Gajewski, T.F., Wang, C.R., and Reiner, S.L. (1998). Helper T cell differentiation is controlled by the cell cycle. Immunity 9, 229-237 .9729043
[12] Breitfeld, D., Ohl, L., Kremmer, E., Ellwart, J., Sallusto, F., Lipp, M., and F?rster, R. (2000). 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 .11104797
[13] Brinkmann, V., Davis, M.D., Heise, C.E., Albert, R., Cottens, S., Hof, R., Bruns, C., Prieschl, E., Baumruker, T., Hiestand, P., (2002). The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 277, 21453-21457 .11967257
[14] Brusselle, G.G., Kips, J.C., Tavernier, J.H., van der Heyden, J.G., Cuvelier, C.A., Pauwels, R.A., and Bluethmann, H. (1994). Attenuation of allergic airway inflammation in IL-4 deficient mice. Clin Exp Allergy 24, 73-80 .8156448
[15] Brüstle, A., Heink, S., Huber, M., Rosenpl?nter, C., Stadelmann, C., Yu, P., Arpaia, E., Mak, T.W., Kamradt, T., and Lohoff, M. (2007). The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol 8, 958-966 .17676043
[16] Busse, W.W., and Lemanske, R.F. Jr. (2001). Asthma. N Engl J Med 344, 350-362 .11172168
[17] Chang, H.C., Sehra, S., Goswami, R., Yao, W., Yu, Q., Stritesky, G.L., Jabeen, R., McKinley, C., Ahyi, A.N., Han, L., (2010). The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol 11, 527-534 .20431622
[18] Cohn, L., Tepper, J.S., and Bottomly, K. (1998). IL-4-independent induction of airway hyperresponsiveness by Th2, but not Th1, cells. J Immunol 161, 3813-3816 .9780144
[19] Corry, D.B., Folkesson, H.G., Warnock, M.L., Erle, D.J., Matthay, M.A., Wiener-Kronish, J.P., and Locksley, R.M. (1996). Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J Exp Med 183, 109-117 .8551213
[20] Yusuf, I., Kageyama, R., Monticelli, L., Johnston, R.J., Ditoro, D., Hansen, K., Barnett, B., and Crotty, S. (2010). Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). J Immunol 185, 190-202 .20525889
[21] Dardalhon, V., Awasthi, A., Kwon, H., Galileos, G., Gao, W., Sobel, R.A., Mitsdoerffer, M., Strom, T.B., Elyaman, W., Ho, I.C., (2008). IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol 9, 1347-1355 .18997793
[22] Dufort, F.J., Bleiman, B.F., Gumina, M.R., Blair, D., Wagner, D.J., Roberts, M.F., Abu-Amer, Y., and Chiles, T.C. (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 .17911579
[23] Fang, T.C., Yashiro-Ohtani, Y., Del Bianco, C., Knoblock, D.M., Blacklow, S.C., and Pear, W.S. (2007). Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity 27, 100-110 .17658278
[24] Fazilleau, N., McHeyzer-Williams, L.J., Rosen, H., and McHeyzer-Williams, M.G. (2009). The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nat Immunol 10, 375-384 .19252493
[25] F?rster, R., Mattis, A.E., Kremmer, E., Wolf, E., Brem, G., and Lipp, M. (1996). A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87, 1037-1047 .8978608
[26] Gessner, A., Blum, H., and R?llinghoff, M. (1993). Differential regulation of IL-9-expression after infection with Leishmania major in susceptible and resistant mice. Immunobiology 189, 419-435 .8125519
[27] Harris, N.L., Watt, V., Ronchese, F., and Le Gros, G. (2002). Differential T cell function and fate in lymph node and nonlymphoid tissues. J Exp Med 195, 317-326 .11828006
[28] Hegazy, A.N., Peine, M., Helmstetter, C., Panse, I., Fr?hlich, A., Bergthaler, A., Flatz, L., Pinschewer, D.D., Radbruch, A., and L?hning, M. (2010). Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions. Immunity 32, 116-128 .20079668
[29] Herrick, C.A., and Bottomly, K. (2003). To respond or not to respond: T cells in allergic asthma. Nat Rev Immunol 3, 405-412 .12766762
[30] Ho, I.C., and Glimcher, L.H. (2002). Transcription: tantalizing times for T cells. Cell 109, S109-S120 .11983157
[31] Ho, I.C., Hodge, M.R., Rooney, J.W., and Glimcher, L.H. (1996). The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. Cell 85, 973-983 .8674125
[32] Hutchins, A.S., Mullen, A.C., Lee, H.W., Sykes, K.J., High, F.A., Hendrich, B.D., Bird, A.P., and Reiner, S.L. (2002). Gene silencing quantitatively controls the function of a developmental trans-activator. Mol Cell 10, 81-91 .12150909
[33] Johnston, R.J., Poholek, A.C., DiToro, D., Yusuf, I., Eto, D., Barnett, B., Dent, A.L., Craft, J., and Crotty, S. (2009). Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006-1010 .19608860
[34] Kaplan, M.H., Schindler, U., Smiley, S.T., and Grusby, M.J. (1996). Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 4, 313-319 .8624821
[35] Kim, J., Woods, A., Becker-Dunn, E., and Bottomly, K. (1985). Distinct functional phenotypes of cloned Ia-restricted helper T cells. J Exp Med 162, 188-201 .3159823
[36] King, I.L., and Mohrs, M. (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 .19380638
[37] Kips, J.C., Brusselle, G.G., Joos, G.F., Peleman, R.A., Devos, R.R., Tavernier, J.H., and Pauwels, R.A. (1995). Importance of interleukin-4 and interleukin-12 in allergen-induced airway changes in mice. Int Arch Allergy Immunol 107, 115-118 .7613115
[38] Kopf, M., Le Gros, G., Coyle, A.J., Kosco-Vilbois, M., and Brombacher, F. (1995). Immune responses of IL-4, IL-5, IL-6 deficient mice. Immunol Rev 148, 45-69 .8825282
[39] Lee, G.R., Fields, P.E., and Flavell, R.A. (2001). Regulation of IL-4 gene expression by distal regulatory elements and GATA-3 at the chromatin level. Immunity 14, 447-459 .11336690
[40] Lee, Y.K., Turner, H., Maynard, C.L., Oliver, J.R., Chen, D., Elson, C.O., and Weaver, C.T. (2009). Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92-107 .19119024
[41] Li, Z., Zhang, Y., Liu, Z., Wu, X., Zheng, Y., Tao, Z., Mao, K., Wang, J., Lin, G., Tian, L., (2011). ECM1 controls T(H)2 cell egress from lymph nodes through re-expression of S1P(1). Nat Immunol 12, 178-185 .21217760
[42] Linterman, M.A., Beaton, L., Yu, D., Ramiscal, R.R., Srivastava, M., Hogan, J.J., Verma, N.K., Smyth, M.J., Rigby, R.J., and Vinuesa, C.G. (2010). IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med 207, 353-363 .20142429
[43] Liu, Y.J., Joshua, D.E., Williams, G.T., Smith, C.A., Gordon, J., and MacLennan, I.C. (1989). Mechanism of antigen-driven selection in germinal centres. Nature 342, 929-931 .2594086
[44] Liu, Z., Li, Z., Mao, K., Zou, J., Wang, Y., Tao, Z., Lin, G., Tian, L., Ji, Y., Wu, X., (2009). Dec2 promotes Th2 cell differentiation by enhancing IL-2R signaling. J Immunol 183, 6320-6329 .19880450
[45] Lommatzsch, M., Julius, P., Kuepper, M., Garn, H., Bratke, K., Irmscher, S., Luttmann, W., Renz, H., Braun, A., and Virchow, J.C. (2006). The course of allergen-induced leukocyte infiltration in human and experimental asthma. J Allergy Clin Immunol 118, 91-97 .16815143
[46] MacLennan, I.C. (1994). Germinal centers. Annu Rev Immunol 12, 117-139 .8011279
[47] Mandala, S., Hajdu, R., Bergstrom, J., Quackenbush, E., Xie, J., Milligan, J., Thornton, R., Shei, G.J., Card, D., Keohane, C., (2002). Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346-349 .11923495
[48] Martinez-Valdez, H., Guret, C., de Bouteiller, O., Fugier, I., Banchereau, J., and Liu, Y.J. (1996). Human germinal center B cells express the apoptosis-inducing genes Fas, c-myc, P53, and Bax but not the survival gene bcl-2. J Exp Med 183, 971-977 .8642300
[49] Medoff, B.D., Thomas, S.Y., and Luster, A.D. (2008). T cell trafficking in allergic asthma: the ins and outs. Annu Rev Immunol 26, 205-232 .18304002
[50] Mohrs, M., Blankespoor, C.M., Wang, Z.E., Loots, G.G., Afzal, V., Hadeiba, H., Shinkai, K., Rubin, E.M., and Locksley, R.M. (2001). Deletion of a coordinate regulator of type 2 cytokine expression in mice. Nat Immunol 2, 842-847 .11526400
[51] Moreau, J.F., Dechanet-Merville, J., and Taupin, J.L. (2000). T cells and cellular immunity; T receptors (structure, diversity, repertory); differentiation antigens (CD4, CD8); activation; auxillary T cells and immunoregulation; lymphokines (interferons, TNF, IL-1, IL-2, IL-4) and cytotoxicity; concept of cellular immunity deficit. Rev Prat 50, 2183-2193 .11213465
[52] Mosmann, T.R., Cherwinski, H., Bond, M.W., Giedlin, M.A., and Coffman, R.L. (1986). Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136, 2348-2357 .2419430
[53] Mullen, A.C., High, F.A., Hutchins, A.S., Lee, H.W., Villarino, A.V., Livingston, D.M., Kung, A.L., Cereb, N., Yao, T.P., Yang, S.Y., (2001). Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292, 1907-1910 .11397944
[54] Murphy, K.M., and Reiner, S.L. (2002). The lineage decisions of helper T cells. Nat Rev Immunol 2, 933-944 .12461566
[55] Nelms, K., Keegan, A.D., Zamorano, J., Ryan, J.J., and Paul, W.E. (1999). The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol 17, 701-738 .10358772
[56] Nurieva, R.I., Chung, Y., Hwang, D., Yang, X.O., Kang, H.S., Ma, L., Wang, Y.H., Watowich, S.S., Jetten, A.M., Tian, Q., (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 .18599325
[57] Nurieva, R.I., Chung, Y., Martinez, G.J., Yang, X.O., Tanaka, S., Matskevitch, T.D., Wang, Y.H., and Dong, C. (2009). Bcl6 mediates the development of T follicular helper cells. Science 325, 1001-1005 .19628815
[58] O’Shea, J.J., Lahesmaa, R., Vahedi, G., Laurence, A., and Kanno, Y. (2011). Genomic views of STAT function in CD4+ T helper cell differentiation. Nat Rev Immunol 11, 239-250 .21436836
[59] Ong, C.T., Sedy, J.R., Murphy, K.M., and Kopan, R. (2008). Notch and presenilin regulate cellular expansion and cytokine secretion but cannot instruct Th1/Th2 fate acquisition. PLoS One 3, e2823.18665263
[60] Ouyang, W., L?hning, M., Gao, Z., Assenmacher, M., Ranganath, S., Radbruch, A., and Murphy, K.M. (2000). Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity 12, 27-37 .10661403
[61] Paul, W.E., and Ohara, J. (1987). B-cell stimulatory factor-1/interleukin 4. Annu Rev Immunol 5, 429-459 .3297106
[62] Reinhardt, R.L., Liang, H.E., and Locksley, R.M. (2009). Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol 10, 385-393 .19252490
[63] Rengarajan, J., Mowen, K.A., McBride, K.D., Smith, E.D., Singh, H., and Glimcher, L.H. (2002). Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J Exp Med 195, 1003-1012 .11956291
[64] Rivera, J., Proia, R.L., and Olivera, A. (2008). The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol 8, 753-763 .18787560
[65] Robinson, D., Hamid, Q., Bentley, A., Ying, S., Kay, A.B., and Durham, S.R. (1993). Activation of CD4+ T cells, increased TH2-type cytokine mRNA expression, and eosinophil recruitment in bronchoalveolar lavage after allergen inhalation challenge in patients with atopic asthma. J Allergy Clin Immunol 92, 313-324 .8349942
[66] Robinson, D.S., Hamid, Q., Ying, S., Tsicopoulos, A., Barkans, J., Bentley, A.M., Corrigan, C., Durham, S.R., and Kay, A.B. (1992). Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 326, 298-304 .1530827
[67] Rothoeft, T., Gonschorek, A., Bartz, H., Anhenn, O., and Schauer, U. (2003). Antigen dose, type of antigen-presenting cell and time of differentiation contribute to the T helper 1/T helper 2 polarization of naive T cells. Immunology 110, 430-439 .14632640
[68] Schaerli, P., Willimann, K., Lang, A.B., Lipp, M., Loetscher, P., and Moser, B. (2000). CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med 192, 1553-1562 .11104798
[69] Schmitt, E., Germann, T., Goedert, S., Hoehn, P., Huels, C., Koelsch, S., Kühn, R., Müller, W., Palm, N., and Rüde, E. (1994). IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma. J Immunol 153, 3989-3996 .7930607
[70] Schwab, S.R., and Cyster, J.G. (2007). Finding a way out: lymphocyte egress from lymphoid organs. Nat Immunol 8, 1295-1301 .18026082
[71] Schweitzer, A.N., Borriello, F., Wong, R.C., Abbas, A.K., and Sharpe, A.H. (1997). Role of costimulators in T cell differentiation: studies using antigen-presenting cells lacking expression of CD80 or CD86. J Immunol 158, 2713-2722 .9058805
[72] Staudt, V., Bothur, E., Klein, M., Lingnau, K., Reuter, S., Grebe, N., Gerlitzki, B., Hoffmann, M., Ulges, A., Taube, C., (2010). Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33, 192-202 .20674401
[73] Szabo, S.J., Kim, S.T., Costa, G.L., Zhang, X., Fathman, C.G., and Glimcher, L.H. (2000). A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655-669 .10761931
[74] Szabo, S.J., Sullivan, B.M., Stemmann, C., Satoskar, A.R., Sleckman, B.P., and Glimcher, L.H. (2002). Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science 295, 338-342 .11786644
[75] Takahashi, Y., Ohta, H., and Takemori, T. (2001). Fas is required for clonal selection in germinal centers and the subsequent establishment of the memory B cell repertoire. Immunity 14, 181-192 .11239450
[76] Tanaka, S., Motomura, Y., Suzuki, Y., Yagi, R., Inoue, H., Miyatake, S., and Kubo, M. (2011). The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in T(H)2 cells. Nat Immunol 12, 77-85 .21131966
[77] Thomas, S.Y., Banerji, A., Medoff, B.D., Lilly, C.M., and Luster, A.D. (2007). Multiple chemokine receptors, including CCR6 and CXCR3, regulate antigen-induced T cell homing to the human asthmatic airway. J Immunol 179, 1901-1912 .17641057
[78] Veldhoen, M., Uyttenhove, C., van Snick, J., Helmby, H., Westendorf, A., Buer, J., Martin, B., Wilhelm, C., and Stockinger, B. (2008). Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9, 1341-1346 .18931678
[79] Walker, C., Bode, E., Boer, L., Hansel, T.T., Blaser, K., and Virchow, J.C. Jr. (1992). Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am Rev Respir Dis 146, 109-115 .1626792
[80] Weaver, C.T., and Hatton, R.D. (2009). Interplay between the TH17 and TReg cell lineages: a (co-)evolutionary perspective. Nat Rev Immunol 9, 883-889 .19935807
[81] Wei, G., Wei, L., Zhu, J., Zang, C., Hu-Li, J., Yao, Z., Cui, K., Kanno, Y., Roh, T.Y., Watford, W.T., (2009). Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155-167 .19144320
[82] Wurster, A.L., Rodgers, V.L., White, M.F., Rothstein, T.L., and Grusby, M.J. (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 .12023955
[83] Yang, X.O., Angkasekwinai, P., Zhu, J., Peng, J., Liu, Z., Nurieva, R., Liu, X., Chung, Y., Chang, S.H., Sun, B., (2009). Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment. Nat Immunol 10, 1260-1266 .19881507
[84] Yang, X.O., Nurieva, R., Martinez, G.J., Kang, H.S., Chung, Y., Pappu, B.P., Shah, B., Chang, S.H., Schluns, K.S., Watowich, S.S., (2008). Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29, 44-56 .18585065
[85] Yu, D., Rao, S., Tsai, L.M., Lee, S.K., He, Y., Sutcliffe, E.L., Srivastava, M., Linterman, M., Zheng, L., Simpson, N., (2009). The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31, 457-468 .19631565
[86] Zaretsky, A.G., Taylor, J.J., King, I.L., Marshall, F.A., Mohrs, M., and Pearce, E.J. (2009). T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J Exp Med 206, 991-999 .19380637
[87] Zhu, J., Yamane, H., and Paul, W.E. (2010). Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 28, 445-489 .20192806
[88] Zotos, D., Coquet, J.M., Zhang, Y., Light, A., D’Costa, K., Kallies, A., Corcoran, L.M., Godfrey, D.I., Toellner, K.M., Smyth, M.J., (2010). IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med 207, 365-378 .20142430