Perturbation of Invariant Natural Killer T cells by the Clonal Hematopoiesis-related inflammatory environment

Abstract Invariant Natural Killer T (iNKT) cells are characterized by a semi-invariant TCR and NK markers. They respond to glycolipid antigens presented the major histocompatibility complex (MHC)-like molecule CD1d. Our single-cell transcriptomic profiling of several tissues identified marrow iNKT as unique subset, possibly modulating homeostasis. However, little is known about their role in hematological malignancies how disease-related environment impacts cells. For example, clonal hematopoiesis indeterminate potential (CHIP) corresponds condition which mutated hematopoietic have an enhanced fitness expansion, increasing risk leukemia other diseases. Loss TET2 CHIP promotes myeloid skewing inflammation. methycytosine dioxygenase catalyzing DNA demethylation genes involved proliferation, differentiation oncogenesis. impact that loss has on lineage output function yet be defined. In our chimeric mouse model CHIP, only 15% mutants differentiate into iNKT. We also observe decrease non-transformed mice, suggesting environmental inhibition. expect these bystander functionally impaired where inflammation leads chromatin rewiring potentially contributing disease. This addressed studying CHIP-exposed transcriptomes accessibility. Understanding molecular basis functional reprogramming will improve clinical outcomes for transplantation development cellular therapies using