Skip to main content
Protein & Cell logoLink to Protein & Cell
. 2011 Sep 9;2(8):604–611. doi: 10.1007/s13238-011-1083-5

Current understanding of Th2 cell differentiation and function

Zhenhu Li 1, Yuan Zhang 1, Bing Sun 1,2,
PMCID: PMC4875329  PMID: 21904976

Abstract

Helper T cell (Th) has been identified as a critical immune cell for regulating immune response since 1980s. The type 2 helper Tcell (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., Sher A. Functional diversity of helper T lymphocytes. Nature. 1996;383:787–793. doi: 10.1038/383787a0. [DOI] [PubMed] [Google Scholar]
  2. Agarwal S., Avni O., Rao A. Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo. Immunity. 2000;12:643–652. doi: 10.1016/S1074-7613(00)80215-0. [DOI] [PubMed] [Google Scholar]
  3. Agarwal S., Rao A. Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity. 1998;9:765–775. doi: 10.1016/S1074-7613(00)80642-1. [DOI] [PubMed] [Google Scholar]
  4. Allen C.D., Okada T., Cyster J.G. Germinal-center organization and cellular dynamics. Immunity. 2007;27:190–202. doi: 10.1016/j.immuni.2007.07.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Amsen D., Antov A., Jankovic D., Sher A., Radtke F., Souabni A., Busslinger M., McCright B., Gridley T., Flavell R.A. Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity. 2007;27:89–99. doi: 10.1016/j.immuni.2007.05.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Amsen D., Blander J.M., Lee G.R., Tanigaki K., Honjo T., Flavell R.A. Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell. 2004;117:515–526. doi: 10.1016/S0092-8674(04)00451-9. [DOI] [PubMed] [Google Scholar]
  7. Angkasekwinai P., Chang S.H., Thapa M., Watarai H., Dong C. Regulation of IL-9 expression by IL-25 signaling. Nat Immunol. 2010;11:250–256. doi: 10.1038/ni.1846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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. 1999;190:1123–1134. doi: 10.1084/jem.190.8.1123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Barolo S., Walker R.G., Polyanovsky A.D., Freschi G., Keil T., Posakony J.W. A notch-independent activity of suppressor of hairless is required for normal mechanoreceptor physiology. Cell. 2000;103:957–969. doi: 10.1016/S0092-8674(00)00198-7. [DOI] [PubMed] [Google Scholar]
  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., et al. TGF-beta induces IL-9 production from human Th17 cells. J Immunol. 2010;185:46–54. doi: 10.4049/jimmunol.1000356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  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., Reiner S.L. Helper T cell differentiation is controlled by the cell cycle. Immunity. 1998;9:229–237. doi: 10.1016/S1074-7613(00)80605-6. [DOI] [PubMed] [Google Scholar]
  12. Breitfeld D., Ohl L., Kremmer E., Ellwart J., Sallusto F., Lipp M., Förster R. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med. 2000;192:1545–1552. doi: 10.1084/jem.192.11.1545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Brinkmann V., Davis M.D., Heise C.E., Albert R., Cottens S., Hof R., Bruns C., Prieschl E., Baumruker T., Hiestand P., et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002;277:21453–21457. doi: 10.1074/jbc.C200176200. [DOI] [PubMed] [Google Scholar]
  14. Brusselle G.G., Kips J.C., Tavernier J.H., van der Heyden J.G., Cuvelier C.A., Pauwels R.A., Bluethmann H. Attenuation of allergic airway inflammation in IL-4 deficient mice. Clin Exp Allergy. 1994;24:73–80. doi: 10.1111/j.1365-2222.1994.tb00920.x. [DOI] [PubMed] [Google Scholar]
  15. Brüstle A., Heink S., Huber M., Rosenplänter C., Stadelmann C., Yu P., Arpaia E., Mak T.W., Kamradt T., Lohoff M. The development of inflammatory T(H)-17 cells requires interferonregulatory factor 4. Nat Immunol. 2007;8:958–966. doi: 10.1038/ni1500. [DOI] [PubMed] [Google Scholar]
  16. Busse W.W., Lemanske R.F., Jr. Asthma. N Engl J Med. 2001;344:350–362. doi: 10.1056/NEJM200102013440507. [DOI] [PubMed] [Google Scholar]
  17. Chang H.C., Sehra S., Goswami R., Yao W., Yu Q., Stritesky G.L., Jabeen R., McKinley C., Ahyi A.N., Han L., et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol. 2010;11:527–534. doi: 10.1038/ni.1867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Cohn L., Tepper J.S., Bottomly K. IL-4-independent induction of airway hyperresponsiveness by Th2, but not Th1, cells. J Immunol. 1998;161:3813–3816. [PubMed] [Google Scholar]
  19. Corry D.B., Folkesson H.G., Warnock M.L., Erle D.J., Matthay M. A., Wiener-Kronish J.P., Locksley R.M. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J Exp Med. 1996;183:109–117. doi: 10.1084/jem.183.1.109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Yusuf I., Kageyama R., Monticelli L., Johnston R.J., Ditoro D., Hansen K., Barnett B., Crotty S. Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150) J Immunol. 2010;185:190–202. doi: 10.4049/jimmunol.0903505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Dardalhon V., Awasthi A., Kwon H., Galileos G., Gao W., Sobel R. A., Mitsdoerffer M., Strom T.B., Elyaman W., Ho I.C., et al. 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. 2008;9:1347–1355. doi: 10.1038/ni.1677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Dufort F.J., Bleiman B.F., Gumina M.R., Blair D., Wagner D.J., Roberts M.F., Abu-Amer Y., Chiles T.C. Cutting edge: IL-4-mediated protection of primary B lymphocytes from apoptosis via Stat6-dependent regulation of glycolytic metabolism. J Immunol. 2007;179:4953–4957. doi: 10.4049/jimmunol.179.8.4953. [DOI] [PubMed] [Google Scholar]
  23. Fang T.C., Yashiro-Ohtani Y., Del Bianco C., Knoblock D.M., Blacklow S.C., Pear W.S. Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity. 2007;27:100–110. doi: 10.1016/j.immuni.2007.04.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Fazilleau N., McHeyzer-Williams L.J., Rosen H., McHeyzer-Williams M.G. The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nat Immunol. 2009;10:375–384. doi: 10.1038/ni.1704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Förster R., Mattis A.E., Kremmer E., Wolf E., Brem G., Lipp M. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell. 1996;87:1037–1047. doi: 10.1016/S0092-8674(00)81798-5. [DOI] [PubMed] [Google Scholar]
  26. Gessner A., Blum H., Röllinghoff M. Differential regulation of IL-9-expression after infection with Leishmania major in susceptible and resistant mice. Immunobiology. 1993;189:419–435. doi: 10.1016/S0171-2985(11)80414-6. [DOI] [PubMed] [Google Scholar]
  27. Harris N.L., Watt V., Ronchese F., Le Gros G. Differential T cell function and fate in lymph node and nonlymphoid tissues. J Exp Med. 2002;195:317–326. doi: 10.1084/jem.20011558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Hegazy A.N., Peine M., Helmstetter C., Panse I., Fröhlich A., Bergthaler A., Flatz L., Pinschewer D.D., Radbruch A., Löhning M. Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions. Immunity. 2010;32:116–128. doi: 10.1016/j.immuni.2009.12.004. [DOI] [PubMed] [Google Scholar]
  29. Herrick C.A., Bottomly K. To respond or not to respond: T cells in allergic asthma. Nat Rev Immunol. 2003;3:405–412. doi: 10.1038/nri1084. [DOI] [PubMed] [Google Scholar]
  30. Ho I.C., Glimcher L.H. Transcription: tantalizing times for T cells. Cell. 2002;109:S109–S120. doi: 10.1016/S0092-8674(02)00705-5. [DOI] [PubMed] [Google Scholar]
  31. Ho I.C., Hodge M.R., Rooney J.W., Glimcher L.H. The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. Cell. 1996;85:973–983. doi: 10.1016/S0092-8674(00)81299-4. [DOI] [PubMed] [Google Scholar]
  32. Hutchins A.S., Mullen A.C., Lee H.W., Sykes K.J., High F.A., Hendrich B.D., Bird A.P., Reiner S.L. Gene silencing quantitatively controls the function of a developmental transactivator. Mol Cell. 2002;10:81–91. doi: 10.1016/S1097-2765(02)00564-6. [DOI] [PubMed] [Google Scholar]
  33. Johnston R.J., Poholek A.C., DiToro D., Yusuf I., Eto D., Barnett B., Dent A.L., Craft J., Crotty S. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science. 2009;325:1006–1010. doi: 10.1126/science.1175870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kaplan M.H., Schindler U., Smiley S.T., Grusby M.J. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996;4:313–319. doi: 10.1016/S1074-7613(00)80439-2. [DOI] [PubMed] [Google Scholar]
  35. Kim J., Woods A., Becker-Dunn E., Bottomly K. Distinct functional phenotypes of cloned Ia-restricted helper T cells. J Exp Med. 1985;162:188–201. doi: 10.1084/jem.162.1.188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. King I.L., Mohrs M. IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J Exp Med. 2009;206:1001–1007. doi: 10.1084/jem.20090313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Kips J.C., Brusselle G.G., Joos G.F., Peleman R.A., Devos R.R., Tavernier J.H., Pauwels R.A. Importance of interleukin-4 and interleukin-12 in allergen-induced airway changes in mice. Int Arch Allergy Immunol. 1995;107:115–118. doi: 10.1159/000236947. [DOI] [PubMed] [Google Scholar]
  38. Kopf M., Le Gros G., Coyle A.J., Kosco-Vilbois M., Brombacher F. Immune responses of IL-4, IL-5, IL-6 deficient mice. Immunol Rev. 1995;148:45–69. doi: 10.1111/j.1600-065X.1995.tb00093.x. [DOI] [PubMed] [Google Scholar]
  39. Lee G.R., Fields P.E., Flavell R.A. Regulation of IL-4 gene expression by distal regulatory elements and GATA-3 at the chromatin level. Immunity. 2001;14:447–459. doi: 10.1016/S1074-7613(01)00125-X. [DOI] [PubMed] [Google Scholar]
  40. Lee Y.K., Turner H., Maynard C.L., Oliver J.R., Chen D., Elson C. O., Weaver C.T. Late developmental plasticity in the T helper 17 lineage. Immunity. 2009;30:92–107. doi: 10.1016/j.immuni.2008.11.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Li Z., Zhang Y., Liu Z., Wu X., Zheng Y., Tao Z., Mao K., Wang J., Lin G., Tian L., et al. ECM1 controls T(H)2 cell egress from lymph nodes through re-expression of S1P(1) Nat Immunol. 2011;12:178–185. doi: 10.1038/ni.1983. [DOI] [PubMed] [Google Scholar]
  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., Vinuesa C.G. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med. 2010;207:353–363. doi: 10.1084/jem.20091738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Liu Y.J., Joshua D.E., Williams G.T., Smith C.A., Gordon J., MacLennan I.C. Mechanism of antigen-driven selection in germinal centres. Nature. 1989;342:929–931. doi: 10.1038/342929a0. [DOI] [PubMed] [Google Scholar]
  44. Liu Z., Li Z., Mao K., Zou J., Wang Y., Tao Z., Lin G., Tian L., Ji Y., Wu X., et al. Dec2 promotes Th2 cell differentiation by enhancing IL-2R signaling. J Immunol. 2009;183:6320–6329. doi: 10.4049/jimmunol.0900975. [DOI] [PubMed] [Google Scholar]
  45. Lommatzsch M., Julius P., Kuepper M., Garn H., Bratke K., Irmscher S., Luttmann W., Renz H., Braun A., Virchow J.C. The course of allergen-induced leukocyte infiltration in human and experimental asthma. J Allergy Clin Immunol. 2006;118:91–97. doi: 10.1016/j.jaci.2006.02.034. [DOI] [PubMed] [Google Scholar]
  46. MacLennan I.C. Germinal centers. Annu Rev Immunol. 1994;12:117–139. doi: 10.1146/annurev.iy.12.040194.001001. [DOI] [PubMed] [Google Scholar]
  47. Mandala S., Hajdu R., Bergstrom J., Quackenbush E., Xie J., Milligan J., Thornton R., Shei G.J., Card D., Keohane C., et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002;296:346–349. doi: 10.1126/science.1070238. [DOI] [PubMed] [Google Scholar]
  48. Martinez-Valdez H., Guret C., de Bouteiller O., Fugier I., Banchereau J., Liu Y.J. 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. 1996;183:971–977. doi: 10.1084/jem.183.3.971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Medoff B.D., Thomas S.Y., Luster A.D. T cell trafficking in allergic asthma: the ins and outs. Annu Rev Immunol. 2008;26:205–232. doi: 10.1146/annurev.immunol.26.021607.090312. [DOI] [PubMed] [Google Scholar]
  50. Mohrs M., Blankespoor C.M., Wang Z.E., Loots G.G., Afzal V., Hadeiba H., Shinkai K., Rubin E.M., Locksley R.M. Deletion of a coordinate regulator of type 2 cytokine expression in mice. Nat Immunol. 2001;2:842–847. doi: 10.1038/ni0901-842. [DOI] [PubMed] [Google Scholar]
  51. Moreau J.F., Dechanet-Merville J., Taupin J.L. 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. 2000;50:2183–2193. [PubMed] [Google Scholar]
  52. Mosmann T.R., Cherwinski H., Bond M.W., Giedlin M.A., Coffman R.L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986;136:2348–2357. [PubMed] [Google Scholar]
  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., et al. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science. 2001;292:1907–1910. doi: 10.1126/science.1059835. [DOI] [PubMed] [Google Scholar]
  54. Murphy K.M., Reiner S.L. The lineage decisions of helper T cells. Nat Rev Immunol. 2002;2:933–944. doi: 10.1038/nri954. [DOI] [PubMed] [Google Scholar]
  55. Nelms K., Keegan A.D., Zamorano J., Ryan J.J., Paul W.E. The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol. 1999;17:701–738. doi: 10.1146/annurev.immunol.17.1.701. [DOI] [PubMed] [Google Scholar]
  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., et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity. 2008;29:138–149. doi: 10.1016/j.immuni.2008.05.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Nurieva R.I., Chung Y., Martinez G.J., Yang X.O., Tanaka S., Matskevitch T.D., Wang Y.H., Dong C. Bcl6 mediates the development of T follicular helper cells. Science. 2009;325:1001–1005. doi: 10.1126/science.1176676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. O’shea J.J., Lahesmaa R., Vahedi G., Laurence A., Kanno Y. Genomic views of STAT function in CD4+ T helper cell differentiation. Nat Rev Immunol. 2011;11:239–250. doi: 10.1038/nri2958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Ong C.T., Sedy J.R., Murphy K.M., Kopan R. Notch and presenilin regulate cellular expansion and cytokine secretion but cannot instruct Th1/Th2 fate acquisition. PLoS One. 2008;3:e2823. doi: 10.1371/journal.pone.0002823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Ouyang W., Löhning M., Gao Z., Assenmacher M., Ranganath S., Radbruch A., Murphy K.M. Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity. 2000;12:27–37. doi: 10.1016/S1074-7613(00)80156-9. [DOI] [PubMed] [Google Scholar]
  61. Paul W.E., Ohara J. B-cell stimulatory factor-1/interleukin 4. Annu Rev Immunol. 1987;5:429–459. doi: 10.1146/annurev.iy.05.040187.002241. [DOI] [PubMed] [Google Scholar]
  62. Reinhardt R.L., Liang H.E., Locksley R.M. Cytokinesecreting follicular T cells shape the antibody repertoire. Nat Immunol. 2009;10:385–393. doi: 10.1038/ni.1715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Rengarajan J., Mowen K.A., McBride K.D., Smith E.D., Singh H., Glimcher L.H. Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J Exp Med. 2002;195:1003–1012. doi: 10.1084/jem.20011128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Rivera J., Proia R.L., Olivera A. The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol. 2008;8:753–763. doi: 10.1038/nri2400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Robinson D., Hamid Q., Bentley A., Ying S., Kay A.B., Durham S.R. 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. 1993;92:313–324. doi: 10.1016/0091-6749(93)90175-F. [DOI] [PubMed] [Google Scholar]
  66. Robinson D.S., Hamid Q., Ying S., Tsicopoulos A., Barkans J., Bentley A.M., Corrigan C., Durham S.R., Kay A.B. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992;326:298–304. doi: 10.1056/NEJM199201303260504. [DOI] [PubMed] [Google Scholar]
  67. Rothoeft T., Gonschorek A., Bartz H., Anhenn O., Schauer U. 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. 2003;110:430–439. doi: 10.1111/j.1365-2567.2003.01758.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Schaerli P., Willimann K., Lang A.B., Lipp M., Loetscher P., Moser B. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med. 2000;192:1553–1562. doi: 10.1084/jem.192.11.1553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Schmitt E., Germann T., Goedert S., Hoehn P., Huels C., Koelsch S., Kühn R., Müller W., Palm N., Rüde E. 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. 1994;153:3989–3996. [PubMed] [Google Scholar]
  70. Schwab S.R., Cyster J.G. Finding a way out: lymphocyte egress from lymphoid organs. Nat Immunol. 2007;8:1295–1301. doi: 10.1038/ni1545. [DOI] [PubMed] [Google Scholar]
  71. Schweitzer A.N., Borriello F., Wong R.C., Abbas A.K., Sharpe A.H. Role of costimulators in T cell differentiation: studies using antigen-presenting cells lacking expression of CD80 or CD86. J Immunol. 1997;158:2713–2722. [PubMed] [Google Scholar]
  72. Staudt V., Bothur E., Klein M., Lingnau K., Reuter S., Grebe N., Gerlitzki B., Hoffmann M., Ulges A., Taube C., et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity. 2010;33:192–202. doi: 10.1016/j.immuni.2010.07.014. [DOI] [PubMed] [Google Scholar]
  73. Szabo S.J., Kim S.T., Costa G.L., Zhang X., Fathman C.G., Glimcher L.H. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000;100:655–669. doi: 10.1016/S0092-8674(00)80702-3. [DOI] [PubMed] [Google Scholar]
  74. Szabo S.J., Sullivan B.M., Stemmann C., Satoskar A.R., Sleckman B.P., Glimcher L.H. Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science. 2002;295:338–342. doi: 10.1126/science.1065543. [DOI] [PubMed] [Google Scholar]
  75. Takahashi Y., Ohta H., Takemori T. Fas is required for clonal selection in germinal centers and the subsequent establishment of the memory B cell repertoire. Immunity. 2001;14:181–192. doi: 10.1016/S1074-7613(01)00100-5. [DOI] [PubMed] [Google Scholar]
  76. Tanaka S., Motomura Y., Suzuki Y., Yagi R., Inoue H., Miyatake S., Kubo M. The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in T(H)2 cells. Nat Immunol. 2011;12:77–85. doi: 10.1038/ni.1966. [DOI] [PubMed] [Google Scholar]
  77. Thomas S.Y., Banerji A., Medoff B.D., Lilly C.M., Luster A.D. Multiple chemokine receptors, including CCR6 and CXCR3, regulate antigen-induced T cell homing to the human asthmatic airway. J Immunol. 2007;179:1901–1912. doi: 10.4049/jimmunol.179.3.1901. [DOI] [PubMed] [Google Scholar]
  78. Veldhoen M., Uyttenhove C., van Snick J., Helmby H., Westendorf A., Buer J., Martin B., Wilhelm C., Stockinger B. Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008;9:1341–1346. doi: 10.1038/ni.1659. [DOI] [PubMed] [Google Scholar]
  79. Walker C., Bode E., Boer L., Hansel T.T., Blaser K., Virchow J. C., Jr. Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am Rev Respir Dis. 1992;146:109–115. doi: 10.1164/ajrccm/146.1.109. [DOI] [PubMed] [Google Scholar]
  80. Weaver C.T., Hatton R.D. Interplay between the TH17 and TReg cell lineages: a (co-)evolutionary perspective. Nat Rev Immunol. 2009;9:883–889. doi: 10.1038/nri2660. [DOI] [PubMed] [Google Scholar]
  81. Wei G., Wei L., Zhu J., Zang C., Hu-Li J., Yao Z., Cui K., Kanno Y., Roh T.Y., Watford W.T., et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity. 2009;30:155–167. doi: 10.1016/j.immuni.2008.12.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Wurster A.L., Rodgers V.L., White M.F., Rothstein T.L., Grusby M.J. Interleukin-4-mediated protection of primary B cells from apoptosis through Stat6-dependent up-regulation of Bcl-xL. J Biol Chem. 2002;277:27169–27175. doi: 10.1074/jbc.M201207200. [DOI] [PubMed] [Google Scholar]
  83. Yang X.O., Angkasekwinai P., Zhu J., Peng J., Liu Z., Nurieva R., Liu X., Chung Y., Chang S.H., Sun B., et al. Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment. Nat Immunol. 2009;10:1260–1266. doi: 10.1038/ni.1821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  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., et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity. 2008;29:44–56. doi: 10.1016/j.immuni.2008.05.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Yu D., Rao S., Tsai L.M., Lee S.K., He Y., Sutcliffe E.L., Srivastava M., Linterman M., Zheng L., Simpson N., et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity. 2009;31:457–468. doi: 10.1016/j.immuni.2009.07.002. [DOI] [PubMed] [Google Scholar]
  86. Zaretsky A.G., Taylor J.J., King I.L., Marshall F.A., Mohrs M., Pearce E.J. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J Exp Med. 2009;206:991–999. doi: 10.1084/jem.20090303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Zhu J., Yamane H., Paul W.E. Differentiation of effector CD4 T cell populations (*) Annu Rev Immunol. 2010;28:445–489. doi: 10.1146/annurev-immunol-030409-101212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  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., et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med. 2010;207:365–378. doi: 10.1084/jem.20091777. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Protein & Cell are provided here courtesy of Oxford University Press

RESOURCES