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Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3⁺ regulatory T cells

Wei, Jun, Duramad, Omar, Perng, Olivia A., Reiner, Steven L., Liu, Yong-Jun, Qin, F. Xiao-Feng
Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.46 pp. 18169-18174
CD4-positive T-lymphocytes, GATA transcription factors, antigens, autocrine signaling, immune response, interleukin-4, neutralization, transforming growth factor beta
Recent studies have highlighted the importance of peripheral induction of Foxp3-expressing regulatory T cells (Tregs) in the dominant control of immunological tolerance. However, Foxp3⁺ Treg differentiation from naïve CD4⁺ T cells occurs only under selective conditions, whereas the classical T helper (Th) 1 and 2 effector development often dominate T cell immune responses to antigen stimulation in the periphery. The reason for such disparity remains poorly understood. Here we report that Th1/Th2-polarizing cytokines can potently inhibit Foxp3⁺ Treg differentiation from naïve CD4⁺ precursors induced by TGF-β. Furthermore, antigen receptor-primed CD4⁺ T cells are resistant to Treg induction because of autocrine production of IFNγ and/or IL-4, whereas neutralizing IFNγ and IL-4 not only can potentiate TGF-β-mediated Foxp3 induction in vitro but can also enhance antigen-specific Foxp3⁺ Treg differentiation in vivo. Mechanistically, inhibition of Foxp3⁺ Treg development by Th1/Th2-polarizing cytokines involves the activation of Th1/Th2 lineage transcription factors T-bet and GATA-3 through the canonical Stat1-, Stat4-, and Stat6-dependent pathways. Using IFNγ and IL-4 knockouts and retrovirus-mediated transduction of T-bet and GATA-3, we further demonstrate that enforced expression of the Th1/Th2 lineage-specific transcription factors is sufficient to block Foxp3 induction and Treg differentiation independent of the polarizing/effector cytokines. Thus, our study has unraveled a previously unrecognized mechanism of negative cross-regulation of Foxp3⁺ Treg fate choice by Th1/Th2 lineage activities. In addition, these findings also provide an attainable explanation for the general paucity of antigen-triggered de novo generation of Foxp3⁺ Tregs in the periphery.