Implications for CD8 T cell exhaustion

2 The PD-1:PD-L pathway plays a major role in regulating T cell exhaustion during chronic viral infections in animal models as well as in humans and blockade of this pathway can revive exhausted CD8+ T cells. Here we examined the expression of PD-1 and its ligands, PD-L1 and PD-L2 in multiple tissues during the course of chronic viral infection and determined how the amount of PD-1 expressed as well as anatomical location influenced the function of exhausted CD8 T cells. The amount of PD-1 on exhausted CD8 T cells from different anatomical locations did not always correlate with infectious virus, but did reflect viral antigen in some tissues. Moreover, lower expression of PD-L1 in some locations such as the bone marrow (BM) favored survival of PD-1Hi exhausted CD8 T cells suggesting that some anatomical sites might provide a survival niche for subpopulations of exhausted CD8 T cells. Tissue-specific differences in the function of exhausted CD8 T cells were also observed. However, while cytokine production did not strictly correlate with the amount of PD-1 expressed by exhausted CD8 T cells from different tissues, the ability to degranulate and kill were tightly linked to PD-1 expression regardless of anatomical location. These observations have implications for human chronic infections and for therapeutic interventions based on blockade of the PD-1 pathway.