PhD Candidate University of Alabama at Birmingham, United States
Introduction/Rationale: Invariant Natural Killer T (iNKT) cells constitute a non-conventional T cell subset that recognize lipid antigens presented by CD1d. Through modulation of innate and adaptive immune cells, iNKTs perform functions ranging from antitumor effects to immune regulation. However, how iNKTs behave during early hematologic transformation is unclear. Clonal Hematopoiesis of Indeterminate Potential (CHIP) is a common, age-associated premalignant condition characterized by somatic mutations in blood cells. Of these mutations, TET2 predisposes to cancer, systemic inflammation, and dysregulated lipid metabolism. Yet, the impact of TET2 loss on the intrinsic lipidome, CD1d-lipid antigen presentation, and neighboring iNKT biology is unknown. We hypothesized that TET2-deficient CHIP impairs peripheral iNKT homeostasis via inflammation and disrupted lipid antigen presentation.
Methods: For this, we used non-irradiated bone marrow chimeras, where wild-type recipients received Tet2-deficient (Tet2KO) marrow cells.
Results: We showed a progressive loss of peripheral non-mutated iNKT cells. Transcriptomic and epigenetic profiling revealed chronic activation signatures, enhanced TCR signaling, and skewing toward iNKT17 with suppression of iNKT1 programs. Plasma IL-6 and IL-23 were significantly elevated in Tet2KO mice. Single-cell transcriptomics revealed enrichment of IL-6–STAT3 target genes in Tet2-exposed iNKTs, supporting a mechanistic link. ATAC-seq profiling of iNKTs showed increased NFκB motif accessibility, indicating sustained activation. Since activation depends on CD1d-lipid recognition, we found elevated CD1d expression and altered endogenous lipid composition in Tet2KO cells by liquid chromatography–mass spectrometry.
Conclusion: These findings suggest Tet2 regulates immune signaling and the antigenic landscape that shapes iNKT activation. This provides a mechanistic framework for immune evasion in early CHIP and offers novel immunometabolic targets for therapeutic intervention in the aging population.
