IL-7 signalling represses Bcl-6 and the TFH gene program

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• The transcriptional repressor Bcl-6 is crucial for the development of CD4(+) T follicular helper (TFH) and central memory T (TCM) cells.
• Understanding the factors that direct T cell lineage commitment is vital for controlling adaptive immunity.

Purpose of the Study:

• To investigate the role of Interleukin-2 (IL-2) signaling in T helper cell differentiation.
• To elucidate the mechanisms by which T helper 1 (TH1) cells acquire TFH and TCM characteristics.
• To identify the regulatory pathways governing the divergence of TFH and TCM gene programs.

Main Methods:

• Analysis of gene expression in T helper cells under varying cytokine conditions (IL-2, IL-6, IL-7).
• Investigation of signaling pathways, including STAT5 activation, in response to cytokine stimulation.
• Identification of cell populations expressing specific cytokine receptors (IL-6Rα, IL-7R) post-influenza infection.

Main Results:

• Decreased IL-2 signaling induces Bcl-6 upregulation in TH1 cells, initiating both TFH- and TCM-like gene programs.
• Interleukin-6 (IL-6) exposure favors the TFH program, while Interleukin-7 (IL-7) signaling represses TFH genes (Bcl6, Cxcr5) but not TCM genes (Klf2, Sell).
• IL-7-dependent STAT5 activation mediates the repression of Bcl-6.
• Antigen-specific IL-6Rα(+)IL-7R(+) CD4(+) T cells are observed in effector populations late after influenza infection.

Conclusions:

• IL-7 plays a novel role in repressing the TFH gene program, distinct from its role in TCM development.
• Post-effector TH1 cells exhibit a divergent regulatory mechanism, potentially contributing to both cell-mediated and humoral immunity.
• This study reveals a mechanism for generating long-term adaptive immunity through the plasticity of effector T cells.