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Cholesterol promotes autoimmune pathology through T follicular helper cells

Cellular & Molecular Immunology volume 22, pages 951–953 (2025)Cite this article

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A Correction to this article was published on 03 October 2025

The Original Article was published on 25 June 2025

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Wang et al. [5] first studied the gene and protein expression of FXR in the main subsets of immune cells in the peripheral blood of SLE patients. They reported increased FXR expression in Tfh cells from the peripheral blood of SLE patients compared with other immune subsets, suggesting a potentially unique role for FXR in T-cell-driven autoimmunity. Tfh cells are a subset of CD4⁺ T cells crucial for the formation of germinal centers (GCs) and the production of high-affinity antibodies by B cells. In subsequent mechanistic experiments, Wang et al. studied the effect of FXR on Tfh cells. To determine the functional consequences of FXR in Tfh biology, the authors used FXR knockout (Fxr−/−) mice. These mice presented a marked reduction in both Tfh cell numbers and GC formation. This finding was further substantiated in a pristane-induced lupus model, where compared with control mice, FXR-deficient mice presented significantly attenuated lupus pathology, including smaller spleens, decreased proteinuria, and reduced autoantibody levels. These results demonstrated that FXR contributes to lupus pathogenesis through the promotion of aberrant Tfh responses. The next question the authors addressed was how FXR regulates Tfh cells. They performed RNA sequencing of Tfh cells isolated from wild-type and Fxr−/− mice. Transcriptomic analysis revealed that FXR regulates genes involved in cholesterol biosynthesis and homeostasis, which in turn influences Tfh cell proliferation and survival. This link between lipid metabolism and immune cell function underscores the concept of broad crosstalk between metabolic processes and autoimmunity. Finally, to assess the translational relevance of these findings, they tested the therapeutic potential of targeting FXR signaling in vivo. The bile acid derivative UDCA, a clinically approved drug known to inhibit FXR signaling, was administered orally to mice in which lupus was induced by pristane and to MRL.lpr mice, which develop lupus spontaneously. In both settings, treatment led to a significant reduction in disease severity, characterized by fewer Tfh and GC B cells, lower serum levels of autoantibodies, and overall improved clinical outcomes. These promising results point to FXR as an important therapeutic target in SLE and highlight the potential of repurposing FXR-modulating drugs, such as UDCA, to treat autoimmune diseases.

Although the rapid translation of basic science findings to clinically relevant therapeutic tools is exciting, it is essential to acknowledge its limitations and questions that were not addressed by this study. First, while the FXR inhibitor UDCA has demonstrated therapeutic efficacy in pristane-induced and MRL/lpr lupus models, it has previously failed to significantly benefit NZB × NZW F1 lupus-prone mice [6]. This discrepancy raises important concerns about the influence of pathogenetic heterogeneity, which is prevalent in patients with SLE and suggests that UDCA may offer clinical benefit only in a fraction of patients. Second, the current findings are based on murine models, which, although they provide valuable mechanistic insights, cannot predict whether inhibition of FXR in patients with lupus will have any clinical benefit. Therefore, further studies using ex vivo approaches or lupus-humanized mice are needed prior to planning any clinical trials. It remains to be determined why FXR is upregulated in Tfh cells. It is possible that its upregulation represents previously known biochemical and molecular pathways [7] operating in multiple immune cells or aberrant pathways limited to the expression of FXR in Tfh cells. Along these lines, it is important to know whether global targeting of FXR affects the function of other immune cells. Addressing these questions will be critical to fully understand the role of FXR in SLE and to evaluate its value as a therapeutic target.

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  1. Department of Medicine, Beth Isarael Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Wei Li & George C. Tsokos

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  1. Wei Li
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Correspondence to Wei Li.

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Li, W., Tsokos, G.C. Cholesterol promotes autoimmune pathology through T follicular helper cells. Cell Mol Immunol 22, 951–953 (2025). https://doi.org/10.1038/s41423-025-01319-1

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