IL-7 signalling represses Bcl-6 and the TFH 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-6R alpha 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-6R alpha+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.