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 SIRPG, followed by suboptimal TCR stimulation. Differentiation status, transcription factor expression, and effector cytokine production were measured using flow cytometry. CD47 blockade was used to assess ligand dependency. RESULTS: Low SIRPγ expression on CD8 T-cells was associated with increased frequencies of CD27(-)CD45RO(+) effector-like and CD27(-)CD45RO(-) terminally differentiated CD8 T-cells. SIRPG knockdown induced effector-like differentiation, with increased CD45RO and T-bet expression and elevated TNF-α, IFN-γ, and Granzyme B production. This effect was not recapitulated by CD47 blockade, suggesting a CD47-independent regulatory mechanism. 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.