GPR41 and GPR43 regulate CD8⁺ T cell priming during herpes simplex virus type 1 infection

Area of Science:

• Immunology
• Microbiology
• Metabolomics

Background:

• Naïve CD8+ T cells require complex differentiation for viral control and memory formation.
• Microbiota-derived metabolites influence T cell function, but their role in CD8+ T cell differentiation is not fully understood.

Purpose of the Study:

• To investigate the role of G protein-coupled receptors (GPR) 41 and 43, which bind short-chain fatty acids (SCFAs), in CD8+ T cell priming during herpes simplex virus type 1 (HSV-1) infection.
• To determine if GPR41 and GPR43 expression on CD8+ T cells is essential for anti-viral immunity.

Main Methods:

• Utilized GPR41/43-deficient mice to study CD8+ T cell responses to epicutaneous HSV-1 infection.
• Assessed antigen-elicited production of key cytokines (IFN-γ, TNF-α) and cytotoxic molecules (granzyme B, perforin).
• Analyzed CD8+ T cell differentiation into memory precursors.
• Employed conditional gene expression to restore GPR41/43 exclusively in HSV-specific CD8+ T cells.

Main Results:

• HSV-specific CD8+ T cells in GPR41/43-deficient mice showed impaired production of IFN-γ, TNF-α, granzyme B, and perforin.
• These T cells also exhibited defective differentiation into memory precursors.
• Restoring GPR41 and GPR43 expression solely on HSV-specific CD8+ T cells rescued the defect in controlling HSV-1 infection.

Conclusions:

• GPR41 and GPR43 play critical roles in CD8+ T cell differentiation and the development of anti-viral immunity.
• Metabolite sensing by CD8+ T cells, mediated by GPR41/43, is vital for fine-tuning anti-viral responses.
• These findings highlight the importance of the gut microbiota-immune system axis in adaptive immunity.