Severely exhausted CD8 T cells are refractory to rescue by PD-1 blockade, but re-invigorate following concomitant CD4 T cell depletion in vivo (P6097)

Abstract

Abstract Blockade of the inhibitory PD-1 receptor during chronic infections and cancers has been promising at restoring CD8 T cell function, but it is currently unknown if this functional rescue is optimal during a specific stage of the process of T cell exhaustion. In a model of lifelong LCMV infection in mice, we showed that there is an early phase when PD-1 blockade is able to induce robust rescue of exhausted CD8 T cell responses. As the infection progresses, however, most of the severely exhausted cells become refractory to rescue by PD-1 blockade. This indicated a continuous accumulation of more terminally differentiated virus-specific T cells that underwent a T cell exhaustion program that was regulated by additional inhibitory pathways. This progressive decrease in CD8 T cell rescue potential was associated with a gradual increase in CD4+ Tregs. Interestingly, PD-1 blockade together with transient CD4 depletion during the late stage of chronic infection was able to re-invigorate severely exhausted CD8 T cells and enhance antiviral control. Importantly, whole CD4 depletion did not result in fulminant autoimmune-mediated death that is typically observed following specific Treg ablation. These data suggest that a crucial interplay exists between the PD-1 pathway and CD4+ Tregs at modulating CD8 T cell exhaustion. Our findings may also help to improve immune prophylaxis regimens in patients who remain refractory to PD-1 blockade therapy during chronic infections and cancer.