Fas/FasL signaling is critical for the survival of exhausted antigen-specific CD8 T cells during tumor immune response.

Antigen (Ag)-specific activated CD8 T cells are critical for tumor elimination but become exhausted, and thus, dysfunctional during immune response against the tumor due to chronic antigen stimulation. The signaling of immune checkpoint receptors is known to be a critical component in this exhaustion; however, the fate of these exhausted CD8 T cells remains unclear. Therefore, to elucidate this, we followed the fate of Ag-specific CD8 T cells by directly visualizing them using MHC class I tetramers coupled with ovoalubumin in C57BL/6 mice inoculated with EG.7. We found that the number of generated Ag-specific activated CD8 T cells decreased via apoptosis during a prolonged tumor immune response. However, the number of Ag-specific CD8 T cells was significantly higher in Fas ligand (FasL)-dysfunctional gld mice than in control mice, resulting in suppressed tumor growth. In contrast, the enforced expression of Bcl-2 failed to rescue apoptosis of the exhausted CD8 T cells following EG.7 inoculation. These results suggest that Fas/FasL signaling is critical for the survival of exhausted CD8 T cells during the tumor immune response.