Cytokines of the γc family control CD4+ T cell differentiation and function

Naive CD4+ T cells undergo massive proliferation and differentiation into at least four distinct helper T cell subsets after recognition of foreign antigen–derived peptides presented by dendritic cells. Each helper T cell subset expresses a distinct set of genes that encode unique transcription factor(s), as well as hallmark cytokines. The cytokine environment created by activated CD4+ T cells, dendritic cells and/or other cell types during the course of differentiation is a major determinant for the helper T cell fate. This Review focuses on the role of cytokines of the common γ-chain (γc) family in the determination of the effector helper T cell phenotype that naive CD4+ T cells adopt after being activated and in the function of these helper T cells.

[1]  Penelope A. Morel,et al.  Dominant Role of Antigen Dose in CD4+Foxp3+ Regulatory T Cell Induction and Expansion1 , 2009, The Journal of Immunology.

[2]  L. Berg,et al.  Janus-kinase-3-dependent signals induce chromatin remodeling at the Ifng locus during T helper 1 cell differentiation. , 2008, Immunity.

[3]  Li Li,et al.  Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3 , 2003, The Journal of experimental medicine.

[4]  N. Fazilleau,et al.  The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding , 2009, Nature Immunology.

[5]  M. Nakahira,et al.  Basophils contribute to TH2-IgE responses in vivo via IL-4 production and presentation of peptide–MHC class II complexes to CD4+ T cells , 2009, Nature Immunology.

[6]  Prabir Ray,et al.  A critical role for NF-κB in Gata3 expression and TH2 differentiation in allergic airway inflammation , 2001, Nature Immunology.

[7]  M. Waterman,et al.  T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-γ , 2009, Nature Immunology.

[8]  M. Horton,et al.  Regulation of immune responses by mTOR. , 2012, Annual review of immunology.

[9]  M. Farrar,et al.  IL-2, -7, and -15, but Not Thymic Stromal Lymphopoeitin, Redundantly Govern CD4+Foxp3+ Regulatory T Cell Development1 , 2008, The Journal of Immunology.

[10]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[11]  H. Hammad,et al.  Inflammatory dendritic cells—not basophils—are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen , 2010, The Journal of experimental medicine.

[12]  J. Bazan,et al.  Structural design and molecular evolution of a cytokine receptor superfamily. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[13]  L. Samelson,et al.  A LAT Mutation That Inhibits T Cell Development Yet Induces Lymphoproliferation , 2002, Science.

[14]  Linjiang Zhu,et al.  A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. , 2009, Immunity.

[15]  S. Crotty,et al.  Follicular helper CD4 T cells (TFH). , 2011, Annual review of immunology.

[16]  M. Farrar,et al.  IL-2 Receptor β-Dependent STAT5 Activation Is Required for the Development of Foxp3+ Regulatory T Cells1 , 2007, The Journal of Immunology.

[17]  J. O’Shea,et al.  Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5 , 2011, Nature Immunology.

[18]  N. Schmitz,et al.  CD40–CD40L cross-talk integrates strong antigenic signals and microbial stimuli to induce development of IL-17-producing CD4+ T cells , 2009, Proceedings of the National Academy of Sciences.

[19]  Burton E. Barnett,et al.  IL-21 and IL-6 Are Critical for Different Aspects of B Cell Immunity and Redundantly Induce Optimal Follicular Helper CD4 T Cell (Tfh) Differentiation , 2011, PloS one.

[20]  A. Liston,et al.  Decreased T-cell receptor signaling through CARD11 differentially compromises forkhead box protein 3-positive regulatory versus T(H)2 effector cells to cause allergy. , 2011, The Journal of allergy and clinical immunology.

[21]  W. Paul,et al.  Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells to generate a Th2-inducing cytokine environment , 2005, The Journal of experimental medicine.

[22]  A. Sher,et al.  Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. , 2007, Immunity.

[23]  Chen Dong,et al.  TH17 cells in development: an updated view of their molecular identity and genetic programming , 2008, Nature Reviews Immunology.

[24]  C. Mackay,et al.  The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. , 2009, Immunity.

[25]  Federica Sallusto,et al.  Follicular B Helper T Cells Express Cxc Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production , 2000, The Journal of experimental medicine.

[26]  D. Sojka,et al.  Regulatory T Cell + Susceptibility to CD 25 Early Kinetic Window of Target T Cell and , 2005 .

[27]  S. Blacklow,et al.  Notch directly regulates Gata3 expression during T helper 2 cell differentiation. , 2007, Immunity.

[28]  S. Kaech,et al.  In Vivo Regulation of Bcl6 and T Follicular Helper Cell Development , 2010, Journal of Immunology.

[29]  L. Ivashkiv,et al.  Inhibition of Interleukin 2 Signaling and Signal Transducer and Activator of Transcription (Stat)5 Activation during T Cell Receptor–Mediated Feedback Inhibition of T Cell Expansion , 1999, The Journal of experimental medicine.

[30]  L. Xerri,et al.  High expression of the inhibitory receptor BTLA in T-follicular helper cells and in B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia. , 2009, American journal of clinical pathology.

[31]  R. Locksley,et al.  Genetic analysis of basophil function in vivo , 2011, Nature Immunology.

[32]  D. Voehringer,et al.  Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance , 2010, Nature Immunology.

[33]  K. Oestreich,et al.  Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile , 2012, Nature Immunology.

[34]  K. Murphy,et al.  Notch and Presenilin Regulate Cellular Expansion and Cytokine Secretion but Cannot Instruct Th1/Th2 Fate Acquisition , 2008, PloS one.

[35]  S. Ishihara,et al.  CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation–mediated apoptosis of effector CD4+ T cells , 2007, Nature Immunology.

[36]  M. Boothby,et al.  Opposing Roles for RelB and Bcl-3 in Regulation of T-Box Expressed in T Cells, GATA-3, and Th Effector Differentiation 1 , 2005, The Journal of Immunology.

[37]  R. J. Hocking,et al.  TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. , 2006, Immunity.

[38]  B. Everts,et al.  Omega-1, a glycoprotein secreted by Schistosoma mansoni eggs, drives Th2 responses , 2009, The Journal of experimental medicine.

[39]  R. D. Hatton,et al.  Transforming growth factor-β induces development of the TH17 lineage , 2006, Nature.

[40]  A. Kulkarni,et al.  A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells , 2008, Nature Immunology.

[41]  W. Paul,et al.  Stat5 activation plays a critical role in Th2 differentiation. , 2003, Immunity.

[42]  A. Rudensky,et al.  A function for interleukin 2 in Foxp3-expressing regulatory T cells , 2005, Nature Immunology.

[43]  W. Paul,et al.  Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. , 2008, Journal of immunology.

[44]  Jeffrey A. Diamond,et al.  STAT5 is a potent negative regulator of TFH cell differentiation , 2012, The Journal of experimental medicine.

[45]  Richard A Flavell,et al.  The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells , 1997, Cell.

[46]  V. Kuchroo,et al.  Induction and effector functions of TH17 cells , 2008, Nature.

[47]  Burton E. Barnett,et al.  Bcl6 and Blimp-1 Are Reciprocal and Antagonistic Regulators of T Follicular Helper Cell Differentiation , 2009, Science.

[48]  F. Liew,et al.  IMMUNE RESPONSE TO CHEMICALLY MODIFIED FLAGELLIN , 1972, The Journal of experimental medicine.

[49]  S. Constant,et al.  Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. , 1997, Annual review of immunology.

[50]  T. Waldmann,et al.  IL-15Rα Recycles and Presents IL-15 In trans to Neighboring Cells , 2002 .

[51]  Joanna M. Roberts,et al.  In vivo studies fail to reveal a role for IL-4 or STAT6 signaling in Th2 lymphocyte differentiation , 2008, Proceedings of the National Academy of Sciences.

[52]  Ming O. Li,et al.  Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development. , 2010, Immunity.

[53]  R. Nurieva,et al.  Bcl6 Mediates the Development of T Follicular Helper Cells , 2009, Science.

[54]  L. Molinero,et al.  High TCR Stimuli Prevent Induced Regulatory T Cell Differentiation in a NF-κB–Dependent Manner , 2011, The Journal of Immunology.

[55]  D. Littman,et al.  The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells , 2006, Cell.

[56]  Hongbo Chi,et al.  Regulation and function of mTOR signalling in T cell fate decisions , 2012, Nature Reviews Immunology.

[57]  E. Pearce,et al.  MHC class II–dependent basophil–CD4+ T cell interactions promote TH2 cytokine–dependent immunity , 2009, Nature Immunology.

[58]  H. Weiner,et al.  Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells , 2006, Nature.

[59]  Y. Belkaid,et al.  A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β– and retinoic acid–dependent mechanism , 2007, The Journal of experimental medicine.

[60]  John T. Chang,et al.  Role of Costimulation in the Induction of the IL-12/IL-12 Receptor Pathway and the Development of Autoimmunity , 2000, The Journal of Immunology.

[61]  H. Clevers,et al.  The β-catenin–TCF-1 pathway ensures CD4+CD8+ thymocyte survival , 2001, Nature Immunology.

[62]  S. Crotty,et al.  ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. , 2011, Immunity.

[63]  S. Raghav,et al.  An insight into molecular mechanisms of human T helper cell differentiation , 2008, Annals of medicine.

[64]  L. Hennighausen,et al.  Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. , 2007, Immunity.

[65]  Booki Min,et al.  Conditional deletion of Gata3 shows its essential function in TH1-TH2 responses , 2004, Nature Immunology.

[66]  W. Paul,et al.  Memory CD4+ T Cells: fate determination, positive feedback and plasticity , 2012, Cellular and Molecular Life Sciences.

[67]  A. Weinberg,et al.  IL-4 directs the development of Th2-like helper effectors. , 1990, Journal of immunology.

[68]  Ethan M. Shevach,et al.  Cutting Edge: IL-2 Is Critically Required for the In Vitro Activation of CD4+CD25+ T Cell Suppressor Function , 2004, The Journal of Immunology.

[69]  R. Medzhitov,et al.  Basophils Function as Antigen Presenting Cells for an Allergen-Induced TH2 Response , 2009, Nature Immunology.

[70]  Yuka Kanno,et al.  Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. , 2008, Blood.

[71]  R. Meier,et al.  IL‐21 and IL‐21R are not required for development of Th17 cells and autoimmunity in vivo , 2008, European journal of immunology.

[72]  Burton E. Barnett,et al.  Germinal Center T Follicular Helper Cell IL-4 Production Is Dependent on Signaling Lymphocytic Activation Molecule Receptor (CD150) , 2010, The Journal of Immunology.

[73]  D. Levy,et al.  IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways , 2007, Nature Immunology.

[74]  Y. Belkaid,et al.  Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha. , 2011, Immunity.

[75]  S. Ghosh,et al.  Antigen-Receptor Signaling to Nuclear Factor κB , 2006 .

[76]  W. Leonard,et al.  New insights into the regulation of T cells by γc family cytokines , 2009, Nature Reviews Immunology.

[77]  C. Hsieh,et al.  A two-step process for thymic regulatory T cell development. , 2008, Immunity.

[78]  W. Paul,et al.  Differentiation of Effector CD 4 T Cell Populations ∗ , 2014 .

[79]  T. Fry,et al.  The Many Faces of IL-7: From Lymphopoiesis to Peripheral T Cell Maintenance , 2005, The Journal of Immunology.

[80]  Y. Belkaid,et al.  Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid , 2007, The Journal of experimental medicine.

[81]  E. Shevach,et al.  Cutting Edge: IL-2 Is Essential for TGF-β-Mediated Induction of Foxp3+ T Regulatory Cells , 2007, The Journal of Immunology.

[82]  T. Randall,et al.  Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. , 2012, Immunity.

[83]  D. Hwang,et al.  Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. , 2008, Immunity.

[84]  V. Kuchroo,et al.  The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells , 2009, Nature Immunology.

[85]  W. Paul,et al.  How are TH2-type immune responses initiated and amplified? , 2010, Nature Reviews Immunology.

[86]  A. D. Panopoulos,et al.  Essential autocrine regulation by IL-21 in the generation of inflammatory T cells , 2007, Nature.

[87]  A. Singer,et al.  Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice , 2008, Nature Reviews Immunology.

[88]  J. Cyster,et al.  Role of CXCR5 and CCR7 in Follicular Th Cell Positioning and Appearance of a Programmed Cell Death Gene-1High Germinal Center-Associated Subpopulation1 , 2007, The Journal of Immunology.

[89]  J. Andersen,et al.  The major component in schistosome eggs responsible for conditioning dendritic cells for Th2 polarization is a T2 ribonuclease (omega-1) , 2009, The Journal of experimental medicine.

[90]  Terry B. Strom,et al.  IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells , 2007, Nature.

[91]  R. Noelle,et al.  All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation , 2007, The Journal of experimental medicine.

[92]  Dustin E. Schones,et al.  Priming for T helper type 2 differentiation by interleukin 2-mediated induction of IL-4 receptor α chain expression , 2008, Nature Immunology.

[93]  M. Farrar,et al.  Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. , 2008, Immunity.

[94]  W. Leonard,et al.  Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages , 2011, Nature Immunology.

[95]  N. Taylor,et al.  Molecular and cellular basis of T cell lineage commitment. , 2010, Seminars in immunology.

[96]  Hai Qi,et al.  STAT5 Protein Negatively Regulates T Follicular Helper (Tfh) Cell Generation and Function* , 2012, The Journal of Biological Chemistry.

[97]  P. Loetscher,et al.  Cxc Chemokine Receptor 5 Expression Defines Follicular Homing T Cells with B Cell Helper Function , 2000, The Journal of experimental medicine.

[98]  W. Paul,et al.  Differentiation of effector CD4 T cell populations (*). , 2010, Annual review of immunology.

[99]  P. Gregersen,et al.  Structural biology of shared cytokine receptors. , 2009, Annual review of immunology.

[100]  W. Paul,et al.  Interleukin 2 plays a central role in Th2 differentiation. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[101]  B. Malissen,et al.  Induction of T Helper Type 2 Immunity by a Point Mutation in the LAT Adaptor , 2002, Science.