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, and inhibits TCR-induced proliferation by altering intracellular sterol metabolism. However, the mechanisms by which LXR regulates helper T cell subset differentiation in vivo remains unclear. Here we demonstrate here that LXR is a crucial regulator of follicular helper T (Tfh) cells in vivo. Both mixed bone marrow chimera and antigen-specific T cell adoptive co-transfer studies show a specific increase in Tfh cells among LXRß-deficient CD4+ T cell population in response to immunization and LCMV infection. Mechanistically LXRß-deficient Tfh cells express increased levels of TCF-1 but comparable levels of Bcl6, CXCR5, and PD-1 in comparison with LXRß-sufficient Tfh cells. Loss of LXRß confers inactivation of GSK3ß induced by either AKT/ERK activation or Wnt/ß-catenin pathway, leading to elevated TCF-1 expression in CD4+ T cells. Conversely, ligation of LXR represses TCF-1 expression and Tfh cell differentiation in both murine and human CD4+ T cells. Treatment with an LXR agonist significantly diminishes Tfh cells and the levels of antigen-specific IgG upon immunization. These findings unveil a novel cell-intrinsic regulatory function of LXR in Tfh cell differentiation via controlling GSK3ß-TCF1 pathway, which might be a promising target for pharmacological intervention in Tfh-mediated diseases. Overall design: mRNA profiles of follicular helper T cells from wild type and Nr1h2-/- mice were generated by deep sequencing, singleplicate, using Illumina Truseq