A functional subset of CD8⁺ T cells during chronic exhaustion is defined by SIRPα expression

Prolonged exposure of CD8⁺ T cells to antigenic stimulation, as in chronic viral infections, leads to a state of diminished function termed exhaustion. We now demonstrate that even during exhaustion there is a subset of functional CD8⁺ T cells defined by surface expression of SIRPα, a protein not previously reported on lymphocytes. On SIRPα⁺ CD8⁺ T cells, expression of co-inhibitory receptors is counterbalanced by expression of co-stimulatory receptors and it is only SIRPα⁺ cells that actively proliferate, transcribe IFNγ and show cytolytic activity. Furthermore, target cells that express the ligand for SIRPα, CD47, are more susceptible to CD8⁺ T cell-killing in vivo. SIRPα⁺ CD8⁺ T cells are evident in mice infected with Friend retrovirus, LCMV Clone 13, and in patients with chronic HCV infections. Furthermore, therapeutic blockade of PD-L1 to reinvigorate CD8⁺ T cells during chronic infection expands the cytotoxic subset of SIRPα⁺ CD8⁺ T cells.