FXR inhibition functions as a checkpoint blockade of the pathogenic Tfh cell response in lupus.

Abstract

T follicular helper (Tfh) cells specialize in facilitating germinal center B-cell activation and high-affinity antibody generation, which are crucial in humoral immune responses. However, aberrant control of Tfh cells also contributes to the generation of self-reactive autoantibodies and promotes autoimmune diseases such as systemic lupus erythematosus (SLE). The mechanisms that control proper Tfh expansion remain unclear. Here, we show that farnesoid X receptor (FXR) is relatively upregulated in Tfh cells. Genetic deletion of Fxr restrains Tfh expansion both at steady state and in pristane-induced lupus. As a consequence of these defects, mice lacking Fxr manifested GC dysfunction and decreased plasma cell and autoantibody production, which alleviated nephritis progression in pristane-induced lupus. Mechanistically, FXR intrinsically regulates cholesterol homeostasis in Tfh cells, which subsequently controls Tfh cell proliferation. Preclinical treatment of wild-type (WT) mice with the clinically approved drug ursodeoxycholic acid (UDCA) to reduce FXR signaling mitigated lupus disease progression by repressing Tfh expansion, the GC reaction and autoantibody production. These findings provide a rationale for exploring FXR as a potential therapeutic target for SLE.