IL-7 signalling represses Bcl-6 and the T(FH) gene program

The transcriptional repressor Bcl-6 is linked to the development of both CD4(+) T follicular helper (T(FH)) and central memory T (T(CM)) cells. Here, we demonstrate that in response to decreased IL-2 signalling, T helper 1 (T(H)1) cells upregulate Bcl-6 and co-initiate T(FH)- and T(CM)-like gene programs, including expression of the cytokine receptors IL-6Rα and IL-7R. Exposure of this potentially bi-potent cell population to IL-6 favours the T(FH) gene program, whereas IL-7 signalling represses T(FH)-associated genes including Bcl6 and Cxcr5, but not the T(CM)-related genes Klf2 and Sell. Mechanistically, IL-7-dependent activation of STAT5 contributes to Bcl-6 repression. Importantly, antigen-specific IL-6Rα(+)IL-7R(+) CD4(+) T cells emerge from the effector population at late time points post influenza infection. These data support a novel role for IL-7 in the repression of the T(FH) gene program and evoke a divergent regulatory mechanism by which post-effector T(H)1 cells may contribute to long-term cell-mediated and humoral immunity.