T Follicular Helper Cells Restrain Obesity-Related Metabolic Disease by Damping Intestinal Inflammation

The intestinal immune system is a central modulator of obesity-associated metabolic disease. Particularly, high-affinity intestinal IgA maintains gut homeostasis after its generation in a germinal center (GC) response that requires functional T follicular helper (Tfh) cells in Peyer’s patches (PP). The objective of this study was to determine how obesity affects Tfh function leading to metabolic disease. We investigated the phenotype of Tfh cells in diet-induced obese mice. Obese mice showed enlarged PP featured by an expansion of CXCR5 highICOS highTfh cells. Surprisingly, intestinal Tfh cells in obese mice showed evidence of dysfunction as they expressed substantially lower PD1 and BCL6 but higher CCR7. As a result, the GC response and the generation of IgA +B cells are also defective in obese mice. To determine if Tfh directly regulate intestinal inflammation and metabolic disease during obesity, we fed Tfh-deficient (Cd4 CreBcl6 flox) mice a western diet and investigated their microbiota composition, barrier integrity, and inflammatory status. In the gut, Tfh-deficient obese mice showed a disturbed microbiota, reduced regulatory T cells (Tregs), compromised intestinal barrier, and a loss of the microbiota-derived short-chain fatty acid butyrate. Moreover, we observed exacerbated liver inflammation in Tfh-deficient mice, suggesting a fundamental role for Tfh in dampening inflammation in the gut-liver axis. Mechanistically, Tfh cells express lower levels of insulin receptors and increased Foxo1, suggesting that reduced insulin signaling underlies the dysfunction of Tfh cells during obesity. Overall, our findings highlight an unexpected role for Tfh cells as essential regulators of obesity-related metabolic disease.