NK cells restrain cytotoxic CD8+ T cells in the submandibular gland via PD-1/PD-L1 pathway 2537

Abstract Description 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. The elevated number of CD8+ T cells in the SMG can be recapitulated in NK cell-deficient animals, indicating that NK cells regulate CD8+ T cell homeostasis in this organ. Mechanistically, we demonstrate that NK cells expressing PD-L1 tightly regulate CD8+ T cells in the SMG, uncovering an immunoregulatory function of NK cells in the SMG. When this immunoregulation is disrupted, CD8+ T cells clonally expand and acquire a unique transcriptional profile consistent with TCR activation, effector functions, and exhaustion. 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 immune checkpoint blockade therapies. Funding Sources This work was supported by the following NIH research Grants: R01AI046709 (L.B.), R01AI173163 (L.B.), R24AI072073 (ImmGen), F31DE032593 (S.M.B.), 3R01AI046709-19S1 (L.B.), Brown University Presidential Award (S.M.B.), T32 HL134625 (S.P.R.). Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)