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.