SIRPγ limits effector differentiation of human CD8 T-cells in response to subthreshold TCR-signaling 2266789

Abstract Introduction Signal regulatory protein gamma (SIRPγ) is an immunomodulatory protein that is uniquely expressed on the cell surface of human T cells. Variants in the SIRPγ gene have been associated with type 1 diabetes, relapsing-remitting multiple sclerosis, and the maintenance of a long-term vaccine response. However, the mechanistic contribution of SIRPγ to inflammation remains unclear because its function in the immune system is not fully understood. Methods To investigate the functional role of SIRPγ in human CD8 T-cells, we performed siRNA-mediated knockdown in naïve human CD8+ T-cells. T-cell differentiation, effector responses, and cytokine production were studied by flow cytometry. A CD47 neutralization assay was performed to determine whether this known ligand is required for effector-like differentiation of naïve CD8 T-cells. Results We report that SIRPγ expression varies substantially across individuals and stratifies CD8+ T-cell differentiation states. Individuals with low SIRPγ expression exhibit an increased frequency of CD27⁻CD45RO+ effector-like and CD27⁻CD45RO⁻ terminally differentiated CD8+ T-cells, while high expressors retain a predominance of naïve and central memory cells. Under suboptimal TCR stimulation, SIRPG knockdown drove robust effector-like differentiation marked by increased CD45RO expression, T-bet upregulation, and enhanced production of TNF-α, IFN-γ, and Granzyme B. This phenotype was not recapitulated by CD47 blockade, indicating that SIRPγ modulates differentiation through a CD47-independent mechanism. Conclusion These findings identify SIRPγ as a negative regulator of CD8+ T-cell effector programming under limiting stimulatory conditions. Interindividual variability in SIRPγ expression may influence immune homeostasis and susceptibility to immunopathology, highlighting SIRPγ as a potential therapeutic target in settings of dysregulated T cell responses. Funding Source n/a Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)