LAUSR

Significance Tfh cells are indispensable for effective humoral immunity against infection but detrimental in autoimmune diseases. We demonstrate that LXR, an oxysterol sensor previously known to integrate metabolic and inflammatory signaling, acts as a critical negative regulator of Tfh cell differentiation. LXR deficiency selectively and cell-intrinsically increases Tfh cell differentiation in immunization and viral infection models. Mechanistically, LXR suppresses TCF-1, a transcription factor required for the early Tfh lineage program, by regulating both TCR-mediated and Wnt/β-catenin-mediated inactivation of GSK3β. Since LXR also suppresses human Tfh cell differentiation, our findings accentuate the possibility of targeting LXR to treat Tfh cell-related diseases in humans.