Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile

Abstract

SUMMARYT-bet and Bcl-6 are required to establish TH1 or TFH gene expression profiles, respectively. Here, we demonstrated that high interleukin 2 (IL-2) concentrations inhibited Bcl-6 expression in polarized TH1 cells. Mechanistically, the low amounts of Bcl-6 normally found in effector TH1 cells could not repress its target genes because a T-bet-Bcl-6 complex masked the Bcl-6 DNA-binding domain. TH1 cells increased their Bcl-6/T-bet ratio in response to limiting IL-2 conditions, allowing excess Bcl-6 to repress its direct target Prdm1 (which encodes Blimp-1). The Bcl-6-dependent repression of Blimp-1 effectively induced a partial TFH-profile because Blimp-1 directly repressed a subset of TFH-signature genes, including Cxcr5. Taken together, IL-2-signaling regulates the Bcl-6-Blimp-1 axis in TH1 cells to maintain flexibility with a TFH-like gene profile.

CD4 T cell differentiation in type 1 diabetes

“…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]. Conversely, it has been shown that under conditions of IL-2 deprivation, Th1 cells can acquire a Tfh phenotype [131]. Thus, the availability of IL-2 in the local environment has significant consequences for the development and homeostasis of the Tfh population.…”

“…Recent data suggest that early T cell differentiation is likely to be even more diverse than was appreciated previously [152], with a broad selection of functional phenotypes being generated, the most useful of which are then expanded selectively. Moreover, intermediate differentiation states exist, including a Tfh-like transitional stage shared by Tfh and Th1 cells [153], and phenotypical conversions are possible, such as the switch from Th1 to Tfh under conditions of limiting IL-2 [131]. These developments argue for a more nuanced view of T cell differentiation in type 1 diabetes that does not focus solely on Th1 cells, but also encompasses the possible involvement of IL-21-producing T cells such as Tfh, as well as T cells co-producing IFN-g and IL-17.…”

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

“…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).…”

“…Each of these domains can associate with specific corepressor complexes in B cells and macrophages. The Bcl6 DNA binding zinc fingers are required for Bcl6 activity in CD4 T cells in cell culture (4,12). The Bcl6 BTB domain participates in Tfh cell differentiation (13), most likely by interacting with BCOR (14) and perhaps other corepressors.…”

Early Development in the Peritoneal Cavity of CD49dhigh Th1 Memory Phenotype CD4+ T Cells with Enhanced B Cell Helper Activity

“…In contrast to other types of polarization, differentiation into T FH cells is independent of Th1, Th2, Th17, and regulatory T cell differentiation programs, as T FH cells with features of other polarized T cells have been recognized (28,29). In particular, considerable flexibility between Th1 and T FH cells has been reported; namely, Th1 cells have been demonstrated to increase their B cell lymphoma 6 (Bcl-6)/T-bet ratio under limiting IL-2 conditions to become T FH -like cells (30). In this study, we dem- adopt some of the early T FH differentiation program in the peritoneal milieu.…”