Tet2 Deficiency Disrupts Conventional Dendritic Cell Maturation and Function 4729

Abstract Description Clonal hematopoiesis of indeterminate potential (CHIP), characterized by somatic mutations in blood cells, is increasingly observed with aging. Specifically, Tet2 mutations, which affect epigenetic regulation, are frequently seen in CHIP and are associated with immune deficiencies, inflammation, and susceptibility to infections. However, how Tet2 mutations in immune cells contribute to these clinical outcomes is unknown. Here, we investigated loss of Tet2 in conventional dendritic cells (cDCs), as these cells are critical mediators of adaptive immune response. Using Tet2 knockout (Tet2KO) marrow in a non-conditioned, transplant congenic model, we analyzed peripheral blood and immune tissues over time. Tet2KO progenitors and their progeny cDCs were significantly increased in both frequency and absolute cell number compared to healthy control chimeric mice, with a threefold increase in cDC2s in the mediastinal lymph nodes (MLNs) and altered cDC2/cDC1 ratios. Transcriptomic analysis revealed alterations in genes for MHC processing, T cell co-stimulation, and cytokine secretion, indicating functional changes to cDC subsets. Finally, we assessed the defects in Tet2KO cDCs on immune response during influenza A infection. Our findings identify actionable pathways in cDCs to enhance immune responses, with potential clinical implications for improving immune function in patients with CHIP-related conditions, like atherosclerosis, cancer risk, diabetes and kidney disease. Funding Sources 5T32AR069516-07, Marks Foundation Endeavor Grant Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)