Molecular mechanisms that control the expression and activity of BcI-6 in TH1cells to regulate flexibility with a TFH-like gene profile

The transcription factors T-bet and BcI-6 are required for the establishment of a T helper type 1 cell (T(H)1 cell) and follicular helper T cell (T-FH cell) gene-expression profile, respectively. Here we found that high concentrations of interleukin 2 (IL-2) inhibited BcI-6 expression in polarized T(H)1 cells. Mechanistically, the low concentrations of BcI-6 normally found in effector T(H)1 cells did not repress its target genes because a T-bet BcI-6 complex masked the BcI-6 DNA-binding domain. T(H)1 cells increased their BcI-6/T-bet ratio in response to limiting IL-2 conditions, which allowed excess BcI-6 to repress its direct target Prdm1 (which encodes the transcriptional repressor Blimp-1). The BcI-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. Thus, IL-2-signaling regulates the BcI-6-Blimp-1 axis in T(H)1 cells to maintain flexibility with a T-FH cell like gene profile.