STAT5 is a potent negative regulator of TFH cell differentiation

Abstract

Interleukin 2, STAT5, and Blimp-1 work together to suppress differentiation of follicular helper T cells in mice.

CD4 T cell differentiation in type 1 diabetes

“…Accordingly, signals generated by the IL-2 receptor during early T cell activation can influence the balance between Tfh differentiation and other effector T cell fates [127,128] via signal transducer and activator of transcription (STAT)-5-dependent skewing of the Bcl6/PR domain zinc finger protein 1 (BLIMP1) ratio [129]. Elegant experiments have used MHC class II tetramers to home in on antigen-specific T cells following influenza infection in mice and have shown that IL-2 administration selectively decreases the number of Tfh cells (CXCR5 1 PD1 1 ), but not other effector T cells (CXCR5 -PD1 -) [130].…”

“…Several studies have implicated persistent antigen presentation in Tfh differentiation [117,143], a notion that might fit with the inability of self-antigens to be cleared in autoimmune settings. Interestingly, Tfh differentiation is subject to regulation by a number of pathways that are linked genetically to autoimmunity, including the CD28/cytotoxic T lymphocyte antigen (CTLA)-4 axis [144][145][146][147][148][149][150], IL-2 [127][128][129][130] and the lymphoid-specific tyrosine phosphatase (LYP) encoded by protein tyrosine phosphatase, non-receptor type 22 (PTPN22) [151]. The link between these loci and disease initiation is complex, but modulation of Tfh differentiation adds an additional consideration to the other known roles of the candidate genes in these locations.…”

Bcl6 middle domain repressor function is required for T follicular helper cell differentiation and utilizes the corepressor MTA3

“…There has been some evidence of competition between Bcl6 and STATs at cis-regulatory elements, including the Prdm1 gene locus (29,30). Prdm1 expression is driven by STAT5 in CD4 T cells (9,31). To determine if Bcl6 acetylation affects STAT competition, STAT3 and STAT5 ChIP assays were performed at Prdm1 BRE.…”

“…In B cells, Blimp1 induces plasma cell differentiation and blocks the GC B-cell differentiation program by repressing Bcl6 (8). This reciprocal antagonism also exists in T cells, as Blimp1 directly inhibits Bcl6 expression and supports differentiation of non-Tfh effector cells (2,(9)(10)(11)(12).…”

A distinct subpopulation of CD25−T-follicular regulatory cells localizes in the germinal centers

“…Conversely, Tfh cells are CD25 lo and BCL6 is known to be a reciprocal regulator of BLIMP-1 (2). As a result, Tfh cells are directly inhibited by IL-2/STAT5-driven induction of BLIMP-1 expression (14,15). In addition, Tfr cells themselves have been described to express BLIMP-1, but its deletion causes their expansion, suggesting that BLIMP-1 acts to inhibit their formation (10), whereas loss of BCL6 results in increased expression of BLIMP-1 by Treg cells (7).…”