ABSTRACT
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 follicular 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 LXRß-deficient CD4+ T cell population in response to immunization and lymphocytic choriomeningitis mammarenavirus (LCMV) infection. Mechanistically, LXRß-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 LXRß-sufficient Tfh cells. Loss of LXRß confers inactivation of GSK3ß induced by either AKT/Extracellular signal-regulated kinase (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. 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 GSK3ß-TCF1 pathway, which may serve as a promising target for pharmacological intervention in Tfh-mediated diseases.
Subject(s)
T Follicular Helper Cells , T-Lymphocytes, Helper-Inducer , Mice , Humans , Animals , Liver X Receptors/genetics , Liver X Receptors/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Germinal Center , T Cell Transcription Factor 1/genetics , Cell DifferentiationABSTRACT
Dyslipidemia is a major cause of cardiovascular diseases which represent a leading cause of death in humans. Diverse immune cells are known to be involved in the pathogenesis of cardiovascular diseases such as atherosclerosis. Conversely, dyslipidemia is known to be tightly associated with immune disorders in humans, as evidenced by a higher incidence of atherosclerosis in patients with autoimmune diseases including psoriasis, rheumatoid arthritis, and systemic lupus erythematosus. Given that the dyslipidemia-related autoimmune diseases are caused by autoreactive T cells and B cells, dyslipidemia seems to directly or indirectly regulate the adaptive immunity. Indeed, accumulating evidence has unveiled that proatherogenic factors can impact the differentiation and function of CD4+ T cells, CD8+ T cells, and B cells. This review discusses an updated overview on the regulation of adaptive immunity by dyslipidemia and proposes a potential therapeutic strategy for immune disorders by targeting lipid metabolism.
