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.

The stable and heritable H3K27-methyl mark suppresses transcription of lineage-specific genes in progenitor cells. During developmental transitions, histone demethylases are required to dramatically alter epigenetic and gene expression states to create new cell-specific profiles. It is unclear why demethylase proteins that antagonize polycomb-mediated repression continue to be expressed in terminally differentiated cells where further changes in H3K27-methylation could be deleterious. In this study, we show that the H3K27-demethylases, Jmjd3 and UTX, mediate a functional interaction between the lineage-defining T-box transcription factor family and a Brg1-containing SWI/SNF remodeling complex. Importantly, Jmjd3 is required for the co-precipitation of Brg1 with the T-box factor, T-bet and this interaction is necessary for Ifng remodeling in differentiated Th1 cells. Thus, Jmjd3 has a required role in general chromatin remodeling that is independent from its H3K27-demethylase potential. This function for H3K27-demethylase proteins may explain their presence in differentiated cells where the epigenetic profile is already established.