PD-1 Mediated Regulation of Unique Activated CD8+ T Cells by NK Cells in the Submandibular Gland
The increasing use of anti-PD-1 immune checkpoint blockade has led to the emergence of immune-related adverse events (irAEs), including dysfunction of the submandibular gland (SMG). In this study, we investigated the immunoregulatory mechanism contributing to the susceptibility of the SMG to irAEs. Here, we found that the SMG of PD-1 deficient mice and anti-PD-L1 treated mice harbor an expanded population of CD8+ T cells. We demonstrate that NK cells expressing PD-L1 tightly regulate CD8+ T cells in the SMG. When this immunoregulation is disrupted, CD8+ T cells clonally expand and acquire a unique transcriptional profile consistent with TCR activation. These clonally expanded cells phenotypically overlapped with cytotoxic GzmK+ CD8+ T autoimmune cells identified in primary Sjögren's syndrome patients. Understanding how NK cells modulate CD8+ T cell activity in the SMG opens new avenues for preventing irAEs in patients undergoing checkpoint blockade therapies. Overall design: T cells were extracted from the submandibular glands of WT and PD-1KO mice, and the spleen of WT mice for transcriptomic, proteomic, and TCR repertoire analysis On August 15, 2025, the Series was reorganized in order to include tissue-specific samples.