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

ABSTRACT: 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 LXRβ-deficient CD4+ T cell population in response to immunization and LCMV infection. Mechanistically LXRβ-deficient Tfh cells express increased levels of TCF-1 but comparable levels of Bcl6, CXCR5, and PD-1 in comparison with LXRβ-sufficient Tfh cells. Loss of LXRβ confers inactivation of GSK3β induced by either AKT/ERK activation or Wnt/β-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 GSK3β-TCF1 pathway, which might be a promising target for pharmacological intervention in Tfh-mediated diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE224303 | GEO | 2023/02/06

REPOSITORIES: GEO