Diet-Derived Fatty Acid Induces Dysfunctional Intestinal Tfh Cells via Elevated KLF2 that Impairs Intestinal Homeostasis and Exacerbates Fatty Liver Disease 4794

Abstract Description Metabolic dysfunction-associated steatohepatitis (MASH) is a severe form of fatty liver disease and a growing cause of liver cancer. The intestinal immune system plays a critical role in maintaining gut-liver homeostasis. T follicular helper (Tfh) cells in Peyer’s Patches (PPs) support germinal center (GC) responses that generate high-affinity intestinal IgA, which is essential for gut homeostasis. Indeed, Tfh-deficient mice showed disrupted intestinal permeability and heightened hepatic inflammation. Using a preclinical mouse model of MASH, we showed that a high-fat high-carbohydrate (HFHC) diet feeding induces an inflamed intestinal microenvironment, with enlarged PPs and expanded but dysfunctional ICOS+ CXCR5+ Tfh-like cells. These Tfh-like cells exhibited defective Tfh phenotype, and elevated KLF2, a transcription factor known to inhibit Tfh function, leading to impaired GC responses, and reduced IgA+ B cells. Conversely, reducing KLF2 expression in CD4 T cells improved Tfh function and alleviated MASH pathology, including hepatic steatosis, inflammation, and fibrosis. Mechanistically, the HFHC diet elevated palmitic acid levels in PPs, impairing TCR signaling in T cells, thus preventing proper KLF2 downregulation in Tfh. These findings underscore the crucial role of intestinal Tfh cells in regulating the gut-liver axis during MASH and identify elevated fatty acid as a key driver of their dysfunction, offering a potential therapeutic target for disease intervention. Funding Sources AHA, AAI postdoctoral fellowship. DK122056, HL155993 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)