Down-regulation of Gfi-1 expression by TGF-beta is important for differentiation of Th17 and CD103+ inducible regulatory T cells.
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 beta, 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.
Zhu
Jinfang
J
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. jfzhu@niaid.nih.gov
Davidson
Todd S
TS
Wei
Gang
G
Jankovic
Dragana
D
Cui
Kairong
K
Schones
Dustin E
DE
Guo
Liying
L
Zhao
Keji
K
Shevach
Ethan M
EM
Paul
William E
WE
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D039001:Integrin alpha Chains / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D015703:Antigens, CD; D017931:DNA Primers; D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; D039001:Integrin alpha Chains; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C091367:alpha E integrins