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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.

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