Liver X receptor controls follicular helper T cell differentiation via repression of TCF-1

Liver X receptor (LXR) is a critical regulator of cholesterol homeostasis that inhibits T cell receptor (TCR)-induced proliferation by altering intracellular sterol metabolism. However, the mechanisms by which LXR regulates helper T cell subset differentiation remain unclear. Here, we demonstrate that LXR is a crucial negative regulator of follicu-lar helper T (Tfh) cells in vivo. Both mixed bone marrow chimera and antigen-specific T cell adoptive cotransfer studies show a specific increase in Tfh cells among LXR(3- deficient CD4+ T cell population in response to immunization and lymphocytic chori-omeningitis mammarenavirus (LCMV) infection. Mechanistically, LXR(3-deficient Tfh cells express augmented levels of T cell factor 1 (TCF-1) but comparable levels of Bcl6, CXCR5, and PD-1 in comparison with those of LXR(3-sufficient Tfh cells. Loss of LXR(3 confers inactivation of GSK3(3 induced by either AKT/Extracellular signal-regulated kinase (ERK) activation or Wnt/(3-catenin pathway, leading to elevated TCF-1 expres-sion in CD4+ T cells. Conversely, ligation of LXR represses TCF-1 expression and Tfh cell differentiation in both murine and human CD4+ T cells. LXR agonist significantly diminishes Tfh cells and the levels of antigen-specific IgG upon immunization. These findings unveil a cell-intrinsic regulatory function of LXR in Tfh cell differentiation via the GSK3(3-TCF1 pathway, which may serve as a promising target for pharmacological intervention in Tfh-mediated diseases.