The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20081666
The Journal of Experimental Medicine, Vol. 206, No. 2, 329-341
The Rockefeller University Press, 0022-1007 $30.00
© Zhu et al.
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ARTICLE

 Down-regulation of Gfi-1 expression by TGF-β is important for differentiation of Th17 and CD103+ inducible regulatory T cells

Jinfang Zhu1, Todd S. Davidson1, Gang Wei3, Dragana Jankovic2, Kairong Cui3, Dustin E. Schones3, Liying Guo1, Keji Zhao3, Ethan M. Shevach1, and William E. Paul1

1 Laboratory of Immunology and 2 Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases and 3 Laboratory of Molecular Immunology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892

CORRESPONDENCE Jinfang Zhu: jfzhu{at}niaid.nih.gov

Growth factor independent 1 (Gfi-1), a transcriptional repressor, is transiently induced during T cell activation. Interleukin (IL) 4 further induces Gfi-1, resulting in optimal Th2 cell expansion. We report a second important function of Gfi-1 in CD4 T cells: prevention of alternative differentiation by Th2 cells, and inhibition of differentiation of naive CD4 T cells to either Th17 or inducible regulatory T (iTreg) cells. In Gfi1–/– Th2 cells, the Rorc, Il23r, and Cd103 loci showed histone 3 lysine 4 trimethylation modifications that were lacking in wild-type Th2 cells, implying that Gfi-1 is critical for epigenetic regulation of Th17 and iTreg cell–related genes in Th2 cells. Enforced Gfi-1 expression inhibited IL-17 production and iTreg cell differentiation. Furthermore, a key inducer of both Th17 and iTreg cell differentiation, transforming growth factor β, repressed Gfi-1 expression, implying a reciprocal negative regulation of CD4 T cell fate determination. Chromatin immunoprecipitation showed direct binding of the Gfi-1–lysine-specific demethylase 1 repressive complex to the intergenic region of Il17a/Il17f loci and to intron 1 of Cd103. T cell–specific Gfi1 conditional knockout mice displayed a striking delay in the onset of experimental allergic encephalitis correlated with a dramatic increase of Foxp3+CD103+ CD4 T cells. Thus, Gfi-1 plays a critical role both in enhancing Th2 cell expansion and in repressing induction of Th17 and CD103+ iTreg cells.

Abbreviations used: ChIP, chromatin immunoprecipitation; cKO, conditional KO; CNS, central nervous system; EAE, experimental allergic encephalitis; Gfi-1, growth factor independent 1; H3K4, histone 3 lysine 4; iTreg, inducible Treg; LSD1, lysine-specific demethylase 1; RV, retroviral vector.


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