Abstract
The transcriptional repressor Bcl-6 is linked to the development of both CD4+ T follicular helper (TFH) and central memory T (TCM) cells. Here, we demonstrate that in response to decreased IL-2 signalling, T helper 1 (TH1) cells upregulate Bcl-6 and co-initiate TFH- and TCM-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 TFH gene program, whereas IL-7 signalling represses TFH-associated genes including Bcl6 and Cxcr5, but not the TCM-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 TFH gene program and evoke a divergent regulatory mechanism by which post-effector TH1 cells may contribute to long-term cell-mediated and humoral immunity.
Highlights
The transcriptional repressor Bcl-6 is linked to the development of both CD4 þ T follicular helper (TFH) and central memory T (TCM) cells
In addition to its required role in TFH cell development, Bcl-6 expression has been implicated in the formation of memory CD4 þ T cells[1,17,19,20]
We examined whether the IL-2-sensitive increase in Bcl-6 expression would result in the upregulation of a memory cell gene program by exposing in vitro generated T helper 1 (TH1) cells to both high and low IL-2 concentrations
Summary
The transcriptional repressor Bcl-6 is linked to the development of both CD4 þ T follicular helper (TFH) and central memory T (TCM) cells. We demonstrate that in response to decreased IL-2 signalling, T helper 1 (TH1) cells upregulate Bcl-6 and co-initiate TFH- and TCM-like gene programs, including expression of the cytokine receptors IL-6Ra and IL-7R. Antigen-specific IL-6Ra þ IL-7R þ CD4 þ 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 TFH gene program and evoke a divergent regulatory mechanism by which post-effector TH1 cells may contribute to long-term cell-mediated and humoral immunity. During the course of an immune response, CD4 þ T helper cells identify invading pathogens, proliferate and secrete cytokines to aid in immune-mediated clearance of infection This results in an initial expansion of effector CD4 þ T cells. The expression of these two receptors allows for trafficking to the T-cell zones of secondary lymphoid areas where TCM cells can participate in cell-mediated immunity by engaging in antigen surveillance
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