Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9–producing subset

Since the discovery of T helper type 1 and type 2 effector T cell subsets 20 years ago, inducible regulatory T cells and interleukin 17 (IL-17)-producing T helper cells have been added to the 'portfolio' of helper T cells. It is unclear how many more effector T cell subsets there may be and to what degree their characteristics are fixed or flexible. Here we show that transforming growth factor-β, a cytokine at the center of the differentiation of IL-17-producing T helper cells and inducible regulatory T cells, 'reprograms' T helper type 2 cells to lose their characteristic profile and switch to IL-9 secretion or, in combination with IL-4, drives the differentiation of 'TH-9' cells directly. Thus, transforming growth factor-β constitutes a regulatory 'switch' that in combination with other cytokines can 'reprogram' effector T cell differentiation along different pathways.

[1]  David C. Gondek,et al.  Mast cells are essential intermediaries in regulatory T-cell tolerance , 2006, Nature.

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

[3]  Antonio Lanzavecchia,et al.  Memory and flexibility of cytokine gene expression as separable properties of human TH1 and TH2 lymphocytes , 2003, Nature Immunology.

[4]  A. O’Garra,et al.  GATA-3 Directly Remodels the IL-10 Locus Independently of IL-4 in CD4+ T Cells , 2006, The Journal of Immunology.

[5]  J. Sedat,et al.  Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. , 2001, Immunity.

[6]  A. O’Garra,et al.  TH1 cells control themselves by producing interleukin-10 , 2007, Nature Reviews Immunology.

[7]  Q. Hamid,et al.  Role of IL-9 in the pathophysiology of allergic diseases. , 2001, The Journal of allergy and clinical immunology.

[8]  A Radbruch,et al.  Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. , 2000, Immunity.

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

[10]  Mitchell Kronenberg,et al.  Constitutive Cytokine mRNAs Mark Natural Killer (NK) and NK T Cells Poised for Rapid Effector Function , 2003, The Journal of experimental medicine.

[11]  R. Flavell,et al.  Cutting Edge: TGF-β Inhibits Th Type 2 Development Through Inhibition of GATA-3 Expression , 2000, The Journal of Immunology.

[12]  J. Renauld,et al.  A cascade of cytokines is responsible for IL-9 expression in human T cells. Involvement of IL-2, IL-4, and IL-10. , 1995, Journal of immunology.

[13]  J. Renauld,et al.  Interleukin-9 Enhances Resistance to the Intestinal Nematode Trichuris muris , 1998, Infection and Immunity.

[14]  M. Veldhoen,et al.  TGFbeta1, a "Jack of all trades": the link with pro-inflammatory IL-17-producing T cells. , 2006, Trends in immunology.

[15]  K. Murphy,et al.  Reversibility of T helper 1 and 2 populations is lost after long-term stimulation , 1996, The Journal of experimental medicine.

[16]  R. Kühn,et al.  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. , 1994, Journal of immunology.

[17]  E. Pearce,et al.  Functional Plasticity in Memory T Helper Cell Responses1 , 2007, The Journal of Immunology.

[18]  R. Grencis,et al.  Gastrointestinal nematode expulsion in IL‐4 knockout mice is IL‐13 dependent , 2000, European journal of immunology.

[19]  Christopher A Hunter,et al.  Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10 , 2007, Nature Immunology.

[20]  W. Khan,et al.  Modulation of Intestinal Muscle Contraction by Interleukin-9 (IL-9) or IL-9 Neutralization: Correlation with Worm Expulsion in Murine Nematode Infections , 2003, Infection and Immunity.

[21]  R. Flavell,et al.  Abrogation of TGFβ Signaling in T Cells Leads to Spontaneous T Cell Differentiation and Autoimmune Disease , 2000 .

[22]  R. Germain,et al.  T cell heterogeneity: firmly fixed, predominantly plastic or merely malleable? , 2008, Nature Immunology.

[23]  L. Staudt,et al.  T helper type 2 inflammatory disease in the absence of interleukin 4 and transcription factor STAT6. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  K. Bussell.  Post-translational modification: Jack of all trades , 2005, Nature Reviews Molecular Cell Biology.

[25]  J. Renauld,et al.  IL-4-independent regulation of in vivo IL-9 expression. , 1997, Journal of immunology.

[26]  A. Rao,et al.  An epigenetic view of helper T cell differentiation , 2003, Nature Immunology.

[27]  J. Letterio.  TGF-β signaling in T cells: roles in lymphoid and epithelial neoplasia , 2005, Oncogene.

[28]  S. Akira,et al.  Interleukin (Il)-18 Promotes the Development of Chronic Gastrointestinal Helminth Infection by Downregulating IL-13 , 2001, The Journal of experimental medicine.

[29]  R. Flavell,et al.  Transforming Growth Factor-β Controls Development, Homeostasis, and Tolerance of T Cells by Regulatory T Cell-Dependent and -Independent Mechanisms , 2006 .

[30]  R. D. Hatton,et al.  Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages , 2005, Nature Immunology.

[31]  T. Mcclanahan,et al.  TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell–mediated pathology , 2007, Nature Immunology.

[32]  R. Coffman,et al.  Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. , 1986, Journal of immunology.