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

Signal regulatory protein gamma (SIRPγ) is a T cell–specific surface receptor in the human immune system with previously undefined function in human CD8 T cell differentiation. 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. To investigate the functional role of SIRPγ, we performed small interfering RNA–mediated knockdown in naïve human CD8 T 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. 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.