Dysfunctional T Follicular Helper Cells Cause Intestinal and Hepatic Inflammation in NASH.

Nonalcoholic steatohepatitis (NASH), characterized by hepatic inflammation and cellular damage, is the most severe form of nonalcoholic fatty liver disease and the fastest-growing indication for a liver transplant. The intestinal immune system is a central modulator of local and systemic inflammation. In particular, Peyer's patches (PPs) contain T follicular helper (Tfh) cells that support germinal center (GC) responses required for the generation of high-affinity intestinal IgA and the maintenance of intestinal homeostasis. However, our understanding of the mechanisms regulating mucosal immunity during the pathogenesis of NASH is incomplete. Here, using a preclinical mouse model that resembles the key features of human disease, we discovered an essential role for Tfh cells in the pathogenesis of NASH. We have found that mice fed a high-fat high-carbohydrate (HFHC) diet have an inflamed intestinal microenvironment, characterized by enlarged PPs with an expansion of Tfh cells. Surprisingly, the Tfh cells in the PPs of NASH mice showed evidence of dysfunction, along with defective GC responses and reduced IgA