Olfr2 Signaling in Dendritic Cells Enhances Antigen Presentation and T Cell Activation Promoting Atherosclerosis 2309405

Abstract Introduction Atherosclerosis is a chronic inflammatory disease driven by dysregulated lipid metabolism and maladaptive interactions between innate and adaptive immune cells. Olfactory receptors (ORs), the largest family of G-protein—coupled receptors, are emerging regulators of vascular inflammation beyond their canonical sensory roles. Olfr2 is expressed in monocytes and macrophages, where it senses the lipid peroxidation product, octanal to activate the NLRP3 inflammasome and promote inflammation; still, its role in other myeloid cells is unclear. Methods Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that coordinate adaptive immune responses; however, whether Olfr2 regulates DC-mediated T cell activation during atherogenesis remains poorly defined. We found that Apoe-/-Olfr2-/- mice fed a high-fat diet (42% calories from fat) for 10 weeks exhibit smaller lymph nodes (LNs) and reduced CD4+ and CD8+ T cell activation, as assessed by CD44 and CD69 expression, compared with Apoe-/- controls. We detected significant Olfr2 expression in CD11c+ CD11b+ DC subsets both in the spleen and LNs. This phenotype was associated with decreased MHC-II and CD86 expression on Olfr2-deficient CD11c+CD11b+ DCs, suggesting impaired APC-T cell signaling. Results To determine whether this defect was APC-intrinsic, we initially assessed T cell activation following anti-CD3/CD28 stimulation and found no differences. Next, we performed co-culture experiments using Nur77-GFP-OT-I CD8+ T cells and WT or Olfr2-/- FLT3 ligand-differentiated bone marrow-derived DCs (BMDCs) under OVA peptide—pulsed and non-pulsed conditions. Conclusion The precise mechanistic role of Olfr2 in antigen presentation, DCs activation, and downstream T cell priming during atherogenesis is poorly elucidated. Our data identify Olfr2 as a possible regulator of DC-driven adaptive immunity in atherosclerosis and suggest that targeting this pathway may limit maladaptive APC-T cell interactions and disease progression. Funding Source n/a Topic Categories Classical and Non-Classical Antigen Presenting Cells (APC)