Direct contact with natural killer cells reprograms monocyte-derived dendritic cells into a tolerogenic phenotype 2157

Abstract Description In inflammatory diseases, monocytes are recruited to inflamed tissues, where they differentiate into macrophages and dendritic cells (DCs). These tissue-infiltrating monocyte-derived DCs and macrophages are key inflammatory myeloid antigen-presenting cells (APCs) due to their heightened capacity to activate T cells and contribute to tissue damage. In this study, we developed an anti-dendritic cell immunoreceptor (DCIR) antibody that promotes direct contact between monocyte-derived DCs and Natural Killer (NK) cells. Our results demonstrate that this both initiates rapid depletion of DCs and reprograms surviving cells into a tolerogenic phenotype. This tolerogenic phenotype was defined by simultaneous upregulation of immunoregulatory factors (IL10, IDO1) and downregulation of stimulatory markers (CD11c, CD40, CD44). We showed that this reprogramming was independent of the antibody-targeted receptors and instead relied on direct NK-DC contact. Previous studies have shown that NK cells can modulate DC phenotype by removing surface markers via post-translational trogocytosis. Our findings further reveal NK-mediated reprogramming of DCs also precisely regulates chromatin accessibility and transcription factor activity, leading to profound gene changes at the transcriptional level. This insight complements the mechanisms for developing DC-targeted antibody therapies and may also provide valuable biomarkers in clinical trials assessing multiple myeloid APC-depleting antibodies. Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)