Molecular mechanisms that control the expression and activity of Bcl-6 in T(H)1 cells to regulate flexibility with a T(FH)-like gene profile

T-bet and Bcl-6 are required to establish T(H)1 or T(FH) gene expression profiles, respectively. Here, we demonstrated that high interleukin 2 (IL-2) concentrations inhibited Bcl-6 expression in polarized T(H)1 cells. Mechanistically, the low amounts of Bcl-6 normally found in effector T(H)1 cells could not repress its target genes because a T-bet-Bcl-6 complex masked the Bcl-6 DNA-binding domain. T(H)1 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 T(FH)-profile because Blimp-1 directly repressed a subset of T(FH)-signature genes, including Cxcr5. Taken together, IL-2-signaling regulates the Bcl-6-Blimp-1 axis in T(H)1 cells to maintain flexibility with a T(FH)-like gene profile.