Genome-Wide Regulatory Analysis Reveals That T-bet Controls Th17 Lineage Differentiation through Direct Suppression of IRF4

Abstract

The complex relationship between Th1 and Th17 cells is incompletely understood. The transcription factor T-bet is best known as the master regulator of Th1 lineage commitment. However, attention is now focused on the repression of alternate T cell subsets mediated by T-bet, particularly the Th17 lineage. It has recently been suggested that pathogenic Th17 cells express T-bet and are dependent on IL-23. However, T-bet has previously been shown to be a negative regulator of Th17 cells. We have taken an unbiased approach to determine the functional impact of T-bet on Th17 lineage commitment. Genome-wide analysis of functional T-bet binding sites provides an improved understanding of the transcriptional regulation mediated by T-bet, and suggests novel mechanisms by which T-bet regulates T helper cell differentiation. Specifically, we show that T-bet negatively regulates Th17 lineage commitment via direct repression of the transcription factor interferon regulatory factor-4 (IRF4). An in vivo analysis of the pathogenicity of T-bet deficient T cells demonstrated that mucosal Th17 responses were augmented in the absence of T-bet, and we have demonstrated that the role of T-bet in enforcing Th1 responses and suppressing Th17 responses are separable. The interaction of the two key transcription factors T-bet and IRF4 during the determination of T cell fate choice significantly advances our understanding of the mechanisms underlying the development of pathogenic T cells.

Phenotypic differences of CD4+ T cells in response to red blood cell immunization in transfused sickle cell disease patients

“…The absence of Tbet has been also reported in numerous diseases and has been associated with augmented Th17 responses . Indeed, Tbet can regulate the Th17 lineage negatively . Therefore, the absence of Tbet expression from CD4 + T cells in alloimmunized patients may be associated with the high frequency of Jk b ‐specific Th17 responses observed in this group: indeed, 55% of the Jk b responder patients presented a Th17 profile.…”

T-bet Regulates Natural Regulatory T Cell Afferent Lymphatic Migration and Suppressive Function

“…The results here (Supplementary Fig. S1A and B) suggested that T-bet does not directly regulate Foxp3 expression; and genome wide analyses have shown that Foxp3 and T-bet do not bind each other’s genes directly(4, 38, 39). Although both bind Cmah, Lrig1, Irf4, Prdm1, Sosc2, and Trat1 , they differently regulate their expression.…”

“…T-bet up-regulates CMAH and LRIG1and down-regulates IRF4, PRDM1, SOSC2, and TRAT1. Foxp3 up-regulates LRIG1, IRF4, SOSC2, and TRAT1 in the thymus; up-regulates PRDM1 in thymus and periphery; and down-regulates CMAH in the periphery(38, 39). Further experiments are warranted to determine whether these shared genetic targets are linked to altered Treg function and migration, and if so, by what mechanisms Foxp3 and T-bet use them to regulate Th1 inflammation.…”

The intestinal microbiota determines the colitis‐inducing potential of T‐bet‐deficient Th cells in mice

“…Similarly to Crohn's disease, transferred T cells differentiate into Th1, Th17, and hybrid Th1/17 cells and cause inflammation by recruiting and activating myeloid effector cells . However, conflicting evidence has been provided as to whether induction of colitis is dependent on expression of the Th1 lineage‐determining transcription factor T‐bet by the Th cells . Here we show that the recipient's intestinal microbiota determines whether T‐bet‐deficient Th cells can induce colitis.…”