Dynamic expression of T-bet and GATA3 by regulatory T cells maintains immune tolerance

Regulatory T (Treg) cells can express the transcription factors T-bet and GATA3 but the function of this expression and whether such cells represent stable subsets is still unknown. By using multiple reporter tools, we show that the expression of T-bet and GATA3 in Treg cells is dynamically influenced by the cytokine environment. Treg cell-specific deletion of either Tbx21 or Gata3 genes singly did not result in loss of Treg cell functions; however, mice with combined deficiency of both genes in Treg cells developed severe autoimmune-like diseases. Loss of Treg cell function was correlated with RORγt transcription factor upregulation and reduced Foxp3 expression. Thus, in the steady state, activated Treg cells transiently upregulate either T-bet or GATA3 to maintain T cell homeostasis. Upon antigen stimulation through their T cell receptor (TCR), naive CD4+ T cells differentiate into distinct effector lineages including type 1 T helper (TH1), type 2 T helper (TH2) and interleukin-17 (IL-17)-producing T helper (TH17) cells; this process is influenced by the strength of TCR signaling as well as the cytokine environment1. The differentiation of each TH lineage is determined by the induction of specific key transcription factors: T-bet is important for the differentiation of TH1 cells2; GATA3 is indispensable for the generation of TH2 cells3; and RORγt plays a critical role in determining the fate of TH17 cells4. Not only do these transcription factors promote the differentiation toward one lineage, they also repress acquisition of other fates. For example, T-bet suppresses the expression and functions of GATA35, thus preventing the activation of an endogenous TH2 differentiation pathway during TH1 differentiation6, 7. T-bet also suppresses RORγt expression by interacting and modulating the function of Runx1, which is an important transcription factor for inducing RORγt expression during TH17 differentiation8, 9. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence: [email protected] Phone: 301-402-6662 Fax: 301-480-7352 . COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. Author contributions: F. Y. performed all the experiments; S. S. and J. E. helped in some experiments and made suggestions to the manuscript; L. F. made the transgenic mouse strains; F. Y. and J. Z. designed the experiments, analyzed the data and wrote the paper. HHS Public Access Author manuscript Nat Immunol. Author manuscript; available in PMC 2015 August 01. Published in final edited form as: Nat Immunol. 2015 February ; 16(2): 197–206. doi:10.1038/ni.3053. A uhor M anscript