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Figure 1: PD-1/PD-L1-mediated cytotoxic T lymphocyte exhaustion during chronic viral infection. During chronic viral infection, the persistent presentation of antigen causes CD8 T cells to highly upregulate PD-1, a T cell coinhibitory receptor. PD-L1, the ligand for PD-1, is also upregulated on APC or resident tissue cells during chronic viral infection. This severe overrepresentation of the inhibitory PD-1/PD-L1 pathway is a major cause of exhaustion in CD8 T cells. Exhausted CD8 T cells are functionally deficient and have decreased proliferative capacity, cytokine production, and cytotoxic capacity and are metabolically deficient. Exhausted CD8 T cells are ineffective at clearing virus and, in turn, the chronic infection persists.