Caveolin-1 restrains pathogenic T follicular helper cell response in primary Sjögren’s syndrome

Abstract T follicular helper (Tfh) cells play a central role in humoral autoimmunity, including primary Sjögren’s syndrome (pSS). However, targeting Tfh cells is challenging in clinical management. Previous studies suggested inducible T­cell co­stimulator (ICOS) directed Tfh cell motility in engaging bystander B cells. Here, we identified a novel function of caveolin-1 (Cav-1) in restraining Tfh cell motility, in which Icos transcription was repressed by peroxisome proliferator-activated receptor alpha (PPARα), unexpectedly, independence of lipid metabolism. In the context of autoimmunity, Cav-1 and PPARα expressions were decreased in CD4+ T cells from pSS patients and mice with experimental SS (ESS), while Cav-1 deficiency significantly exacerbated Tfh cell response and ESS pathology. Importantly, pharmaceutical activation of PPARα with fenofibrate effectively ameliorated ESS in mice with acute or chronic inflammation. These results revealed an unrecognized role of Cav-1/PPARα axis in Tfh cell tolerance, suggesting PPARα as a promising target in the treatment of humoral autoimmunity.