Perturbation of Invariant Natural Killer T cells by the Clonal Hematopoiesis-related inflammatory environment 3936

Abstract Description Invariant Natural Killer T (iNKT) cells are a unique subset of T cells with semi-invariant T cell receptors (TCR) and natural killer (NK) markers. They respond to glycolipid antigens presented by CD1d, and like T helper cells, differentiate into subtypes such as iNKT1, iNKT2, and iNKT17. iNKTs play a key role in both immune response and tissue homeostasis by rapidly releasing cytokines in response to pathological signals. Despite their known functions in various diseases, their role in hematological malignancies remains poorly understood. Clonal Hematopoiesis of Indeterminate Potential (CHIP) is a premalignant condition marked by somatic mutations in blood stem cells, leading to clonal expansion. Loss of the epigenetic modifier TET2 in CHIP results in myeloid skewing and increased inflammation, but its effects on iNKT survival and function have not been explored. In this study, we demonstrate that iNKT cells are reduced in the spleens of CHIP-exposed chimeric mice, suggesting impaired iNKT survival. Transcriptomic and chromatin landscape analysis reveal NFκB activation and a differentiation bias towards iNKT17. Flow cytometry further confirms this shift, which may contribute to the pathogenesis of myeloid malignancies. Given their potential for use in allogeneic cell therapies, understanding the mechanisms underlying iNKT dysfunction in CHIP could enable the development of novel immunotherapeutic strategies to enhance cytotoxic activity and improve therapeutic outcomes. Funding Sources Mark Foundation Endeavor Grant Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)