The PD-1/PD-L1 (B7-H1) pathway in chronic infection-induced cytotoxic T lymphocyte exhaustion

Abstract

Cytotoxic CD8 T lymphocytes (CTLs) play a pivotal role in the control of infection. Activated CTLs, however, often lose effector function during chronic infection. PD-1 receptor and its ligand PD-L1 of the B7/CD28 family function as a T cell coinhibitory pathway and are emerging as major regulators converting effector CTLs into exhausted CTLs during chronic infection with human immunodeficiency virus, hepatitis B virus, hepatitis C virus, and other pathogens capable of establishing chronic infections. Importantly, blockade of the PD-1/PD-L1 pathway is able to restore functional capabilities to exhausted CTLs and early clinical trials have shown promise. Further research will reveal how chronic infection induces upregulation of PD-1 on CTLs and PD-L1 on antigen-presenting cells and other tissue cells and how the PD-1/PD-L1 interaction promotes CTLs exhaustion, which is crucial for developing effective prophylactic and therapeutic vaccination against chronic infections.

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.