ABSTRACT Autoimmune disease is the third most common disease category after cancer and heart disease that afflicts 23.5 million Americans. This grant renewal continues to focus on the role of neutrophil FcγRs in autoimmune diseases. However, it has shifted from understanding the role and regulation of neutrophil FcγRs in neutrophil recruitment following intravascular IgG-immune complex deposition in glomerulonephritis (GN) to examining how engaging FcγRs converts neutrophils into highly immunogenic antigen presenting cells (nAPC) and their contribution to autoimmune disorders effecting the kidney. This new direction is based on our recent studies showing that engaging mouse FcγRs or human FcγRIIA or IIIB on mature neutrophils with IgG-complexed antigen (immune complexes) leads to their differentiation into highly active APCs. These cells are comparable to cDCs in their ability to activate naïve T cells and cross-present soluble antigen to CD8 T cells, properties previously assigned almost exclusively to cDCs. Engaging FcγR with an anti-FcγRIIIB-antigen conjugate recapitulates the activity of immune complexes and its administration in FcγR humanized mice generates nAPCs in vivo that elicit robust acquired immunity. Studies in lupus patient samples indicate that nAPC frequency in blood correlates with clinical disease scores, which suggests that nAPCs are pathogenic. Single cell transcriptional analyses and validation studies implicate the pioneer transcription factor PU.1 in neutrophil to nAPC conversion and suggest that transcriptionally defined neutrophil populations convert to two nAPC subsets with distinct gene signatures and functionality. Furthermore, we provide evidence that FcγR internalization and a defined epigenetic regulator play a key role in conversion. Here we propose to 1) Elucidate the functionality of nAPC subsets and the role of epigenetic regulation in neutrophil to nAPC conversion, 2) Elucidate the route of intracellular trafficking of FcγR bound to antibody-antigen complexes and identify mechanisms of FcγR induced generation of immunogenic nAPCs using CRISPR-Cas9 based genetic screens, and 3) Interrogate the role of nAPCs in Antineutrophil cytoplasmic antibody (ANCA)- associated glomerulonephritis and the effect of antigen-tolerized nAPCs in disease outcomes. Dysregulation of the immune system is the basis of many autoimmune diseases for which current treatments are effective in only a subset of patients and are often neither curative nor durable. Neutrophils with APC markers have been observed in diseases from autoimmune diseases to cancer. Results from this proposal may provide important insights into the molecular and cellular pathways governing neutrophil conversion to immunogenic APCs. This could provide insights into the pathogenesis of many immune related disorders and lay the groundwork for new treatments that potentially non-invasively generate a large pool of antigen carrying APCs designed to elicit tolerance or acq...