Dietary lipids are delivered to Tregs in chylomicrons and determine intestinal Treg survival 2310329

Abstract

Abstract Introduction Regulatory T cells (Tregs) limit intestinal mucosal damage in inflammatory bowel disease (IBD), yet no clinical therapies currently exist to enhance Treg numbers or activity. Foundational studies have shown that fatty acids promote Treg differentiation, proliferation, and suppressive activity. Dietary fat, the largest source of fatty acids, is packaged exclusively into chylomicrons, which are secreted directly into the mesenteric lymph. We hypothesized that chylomicrons regulate intestinal Treg accumulation or function. Methods We cannulated mesenteric lymph from mice, from which we isolated chylomicrons for Treg culture. Analyses of Treg metabolism include radiolabeled tracers, quantitative beta-oxidation assays, and seahorse metabolic flux assays. The mouse models we used are: huAPOC3 transgenic mouse models, which overexpresses huAPOC3 under the human promoter; low density lipoprotein receptor (LDLr) knockout mice; APOC3 knockout mice; and littermate and/or appropriate C57BL6 WT controls. Colitis was modeled with both dextran sodium sulfate (DSS) and T cell transfer colitis in Rag-1 knockouts. All lymphocyte population counting and cytokine staining were conducted via flow cytometry. Results We found that Tregs are capable of endocytosing chylomicron lipids and that chylomicron-derived lipids impair Treg survival. Conversely, reducing chylomicron lipid uptake in vivo–via APOC3 overexpression or Treg-specific LDL receptor knockout–enhance Treg accumulation in the colon and protect mice from colitis. Mechanistically, we discovered that chylomicrons instigate Treg apoptosis, which can be reversed by blocking lipid uptake through excess APOC3. In vivo, these mechanisms can be exploited to protect mice from multiple models of colitis. Conclusion Our study shows that chylomicrons and their lipids are an underappreciated regulator of Tregs in the gut and suggests that postprandial chylomicron metabolism may be a novel target for regulating Treg accumulation in the intestine. Funding Source Rainin Foundation (Synergy Award) and the National Institutes of Health (R01DK118239, R03DK116011 ) Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)