Undergraduate Student Texas Woman's University Farmers Branch, Texas, United States
Disclosure(s):
Xanthie Rodriguez: No financial relationships to disclose
Introduction/Rationale: 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.
