The role of immune checkpoint PD-1 in the submandibular gland

Abstract

Abstract Immune checkpoints play an important role in restraining the immune response, maintaining self-tolerance and preventing excessive collateral damage. Immune checkpoint blockade has revolutionized cancer immunotherapy but can lead to immune related adverse events (IrAEs). Patients receiving programmed cell death protein 1 (PD-1) blockade can develop IrAEs including vitiligo, colitis, endocrinopathies, and Sicca Syndrome, an autoimmune disease affecting the salivary and lacrimal glands. After immune cell activation, PD-1 is upregulated, and PD-1 signaling results in reduced proliferation, cytokine production, and cytotoxicity. PD-1 is expressed on infiltrating lymphocytes of the submandibular gland (SMG) including natural killer (NK) and T cells, and recognizes the ligand, PD-L1. Hyporesponsive immune cells in the SMG are thought to retain the integrity of this delicate tissue, while inadvertently contributing to viral latency. We therefore hypothesized that signaling through coinhibitory receptors, including PD-1, may impact these hyporesponsive effector cells. Our preliminary data indicate that genetic loss of PD-1 results in increased CD8+ T cell number and frequency in the SMG, with greater proliferation status. Given the interplay between self-tolerance and chronic viral control, we also examined the role of PD-1 during latent murine cytomegalovirus (MCMV) infection in the SMG. Interestingly, an increased infiltration of CD8+ T cells in the SMG was also observed during MCMV latency period. These studies of PD-1 on SMG immune cells should provide insights for prevention and treatments of IrAEs and chronic viral infections. This work was supported by the following NIH research Grants: R01 AI46709 (L.B.), R01 AI122217 (L.B.) and a Brown University Presidential Award (S.B.).