PD-1 Mediated Regulation of Unique Activated CD8+T Cells by NK Cells in the Submandibular Gland

Abstract

SummaryThe increasing utilization of anti-PD-1 immune checkpoint blockade (ICB) has led to the emergence of immune-related adverse events (irAEs), including sicca syndrome. Interestingly, we found that the submandibular gland (SMG) of PD-1 deficient mice harbors a large population of CD8+T cells, reminiscing ICB induced sicca. This phenotype was also observed in the SMG of both NK cell-depleted C57BL/6 animals and NK cell-deficient animals. Mechanistically, using mice conditionally deficient for PD-L1 in the NK cell lineage, we discovered that NK cells regulate CD8+T cell homeostasis via the PD-1/PD-L1 axis in this organ. Importantly, single-cell RNA sequencing of PD-1 deficient SMG CD8+T cells reveals a unique transcriptional profile consistent with TCR activation. These cells have limited TCR diversity and phenotypically overlap with GzmK+CD8+T autoimmune cells identified in primary Sjögren’s syndrome patients. These insights into NK cell immunoregulation in the SMG, and the consequences of disrupted CD8+T cell homeostasis, provide opportunities for preventing the development of irAEs.HighlightsElevated CD8+T cells in the submandibular gland (SMG) of PD-1 deficient mice parallel sicca-like irAEs seen in ICB patients.In addition to their previously described hyporesponsive phenotype, NK cells in the SMG regulate CD8+T cell homeostasis through the PD-L1/PD-1 axis.PD-1 deficient SMG CD8+T cells display unique transcriptional profiles associated with proinflammatory functions, TCR activation, interferon stimulation, and exhaustion.Oligoclonal expansion and similarities in TCR sequences indicate T cell activation and a preference for recognizing specific antigens.