T follicular helper (Tfh) cells are crucially involved in the pathogenesis of autoimmune disorders, including Sjögren’s syndrome (SS, also known as Sjögren’s disease), by promoting effector B cell responses. However, targeting Tfh cells remains challenging. In this presentation, we will bring our recent findings in the regulation of Tfh cell, which were highly conserved between humans and mice. 

First, we investigated the role of a scaffold protein caveolin-1 (Cav-1) in disease development and effector T cell dysregulation. Cav-1 deficiency in hematopoietic origin exacerbated mice with experimental SS (ESS). pathology and humoral autoimmunity, together with enhanced Tfh cell responses, while Th17 cells were unaffected. Cav-1-/- Tfh cells exhibited increased motility and follicular localization. RNA-seq revealed impaired peroxisome proliferator-activated receptor alpha (PPARα) pathway in the absence of Cav-1. PPARα served as a downstream transcription factor of Cav-1, which rapidly repressed Icos transcription upon Tfh polarization, interestingly, independent of lipid metabolism. Notably, pharmaceutical activation of PPARα with fenofibrate could suppress human and murine Tfh cells in culture, in ESS mice and in humanized SS mice. 

Second, we turn to bioinformatic analysis of ethnopharmacological treatment in the clinical practice, and identified that calycosin (Caly), a natural flavonoid, effectively suppressed pathogenic Tfh cell responses. Mechanistic studies suggested that Caly served as a First-in-Class inhibitor of the master transcription factor, BATF, in both human and murine CD4+ T cells. Although methotrexate (MTX) is widely used as the first-line medication in the treatment of autoimmune disorders, it mainly suppresses B cell responses but fails to target Tfh cells. Notably, MTX synergized with Caly and significantly attenuated the disease pathology in ESS mice with chronic inflammation, showing signs of disease remission. This synergistic effect was also supported in PBMCs from patients with SS, and further validated in HIS-ESS mice.

Dr. Xiang Lin is an Assistant Professor and Assistant Director in the School of Chinese Medicine at The University of Hong Kong (HKU), as well as an affiliated investigator at the State Key Laboratory of Pharmaceutical Biotechnology.

For over 12 years, Dr. Lin has dedicated his research to understanding the immunopathogenesis of Sjögren’s disease (SjD) and developing novel therapeutic strategies. His contributions include: 1) Developing an inducible mouse model of experimental SjD, which has been instrumental in uncovering the critical roles of immune mediators such as Th17 cells, T follicular helper (Tfh) cells, regulatory B (Breg) cells, and myeloid-derived suppressor cells (MDSCs); 2) Extending this research into a novel humanized mouse model, demonstrating the therapeutic potential of anti-IL-17 therapy for SjD; 3) Discovering and patenting multiple drug candidates derived from medicinal herbs, including flavonoid phenolic compounds that effectively inhibit Tfh cells and synergize with methotrexate in both mouse models and human immune cells from SjD patients. Together, Dr. Lin’s work not only advances the understanding of SjD pathogenesis but also establishes a robust drug screening platform for future therapeutics, offering new hope for patients with this challenging autoimmune disorder.