STAT5 Orchestrates Local Epigenetic Changes for Chromatin Accessibility and Rearrangements by Direct Binding to the TCRγ Locus

Abstract

The transcription factor STAT5, which is activated by IL-7R, controls chromatin accessibility and rearrangements of the TCRγ locus. Although STAT-binding motifs are conserved in Jγ promoters and Eγ enhancers, little is known about their precise roles in rearrangements of the TCRγ locus in vivo. To address this question, we established two lines of Jγ1 promoter mutant mice: one harboring a deletion in the Jγ1 promoter, including three STAT motifs (Jγ1PΔ/Δ), and the other carrying point mutations in the three STAT motifs in that promoter (Jγ1PmS/mS). Both Jγ1PΔ/Δ and Jγ1PmS/mS mice showed impaired recruitment of STAT5 and chromatin remodeling factor BRG1 at the Jγ1 gene segment. This resulted in severe and specific reduction in germline transcription, histone H3 acetylation, and histone H4 lysine 4 methylation of the Jγ1 gene segment in adult thymus. Rearrangement and DNA cleavage of the segment were severely diminished, and Jγ1 promoter mutant mice showed profoundly decreased numbers of γδ T cells of γ1 cluster origin. Finally, compared with controls, both mutant mice showed a severe reduction in rearrangements of the Jγ1 gene segment, perturbed development of γδ T cells of γ1 cluster origin in fetal thymus, and fewer Vγ3+ dendritic epidermal T cells. Furthermore, interaction with the Jγ1 promoter and Eγ1, a TCRγ enhancer, was dependent on STAT motifs in the Jγ1 promoter. Overall, this study strongly suggests that direct binding of STAT5 to STAT motifs in the Jγ promoter is essential for local chromatin accessibility and Jγ/Eγ chromatin interaction, triggering rearrangements of the TCRγ locus.

The neonatal microenvironment programs innate γδ T cells through the transcription factor STAT5

“…Hence, both mice and humans with STAT5-associated deficiencies are severely immunocompromised (24,53). T cells of the γδ lineage are reduced in the thymus and lymphoid tissues of fully STAT5deficient mice (21), and this has been attributed to a failure to successfully rearrange the TCR early during embryonic development (26). However, our data show that γδT17 cells require STAT5 signaling to expand and survive after they exit the thymus.…”

“…However, there are currently no mechanistic data regarding their individual contribution in γδ T cell biology. One of the suggested mechanisms for the dependence of developing γδ T cell progenitors on STAT5 is its ability to induce TCRγ rearrangements, due to 3 highly interspecies-conserved inverted-repeat STAT5 consensus sites within the Tcrg locus (26).…”

The neonatal microenvironment programs conventional and intestinal Tbet+γδT17 cells through the transcription factor STAT5

“…Hence, both mice and humans with STAT5-associated deficiencies are severely immunocompromized (Imada et al, 1998; Kofoed et al, 2003). T cells of the γδ lineage are reduced in the thymus and lymphoid tissues of full STAT5-deficient mice (Hoelbl et al, 2006), and this has been attributed to a failure to successfully rearrange the TCR early during embryonic development (Wagatsuma et al, 2015). However, our data show that γδT17 cells require STAT5 signaling to expand and survive after they exit the thymus.…”

“…However, there is currently no mechanistic data regarding their individual contribution in γδ T cell biology. One of the suggested mechanisms for the dependence of developing γδ T cell progenitors on STAT5 is its ability to induce TCRγ rearrangements, due to three highly interspecies conserved inverted repeat STAT5 consensus sites within the TCRγ locus (Wagatsuma et al, 2015).…”

STAT5 and CD4+ T Cell Immunity

“…These studies definitively demonstrated that the STAT5 hypomorph mice retained significant STAT5 function. Studies with STAT5 knockout mice demonstrated that STAT5 plays a critical role in the development of γδ T cells, as it regulates T-cell receptor (TCR) γ gene rearrangement 26, 27 . Likewise, STAT5 is required for expansion of double-negative thymocytes 25 .…”