SIRPγ modulates effector differentiation of human CD8 T Cells under suboptimal TCR stimulation: implications for immune homeostasis and autoimmunity.

Background: Aberrant CD8 T-cell differentiation contributes to the pathogenesis of autoimmune diseases, and immune-mediated tissue damage. However, the molecular mechanisms that prevent premature effector T cell programming in humans remain incompletely defined. Signal regulatory protein gamma (SIRPγ) is selectively expressed on T-cells in the human immune system. Notably, genetic variants associated with reduced SIRPγ expression have been linked to increased risk of immune-mediated diseases, including type 1 diabetes and multiple sclerosis, but the contribution of SIRPγ to CD8 T-cell dysregulation in these contexts remains unclear. Objective: To determine how inter-individual variation in SIRPγ expression influences immune homeostasis and CD8 T-cell effector programming. Methods: Peripheral blood CD8 T-cells from healthy donors were analyzed for SIRPγ expression and associated differentiation phenotypes. Naïve CD8 T-cells were purified and subjected to siRNA-mediated knockdown of Results: Low SIRPγ expression on CD8 T-cells was associated with increased frequencies of CD27 Conclusion: SIRPγ serves as a negative regulator of CD8 T-cell effector differentiation under suboptimal stimulation. Inter-individual variation in its expression may influence susceptibility to immune dysregulation, positioning it as a potential biomarker and therapeutic target.