T helper (Th)17 cells represent a unique subset of CD4⁺ T cells and are vital for clearance of extracellular pathogens including bacteria and fungi. However, Th17 cells are also involved in orchestrating autoimmunity. By employing quantitative surface proteomics, we found that the evolutionarily conserved prohibitins (PHB1/2) are highly expressed on the surface of both murine and human Th17 cells. Increased expression of PHBs at the cell surface contributed to enhanced CRAF/MAPK activation in Th17 cells. Targeting surface‐expressed PHBs on Th17 cells with ligands such as Vi polysaccharide (Typhim vaccine) inhibited CRAF‐MAPK pathway, reduced interleukin (IL)‐17 expression and ameliorated disease pathology with an increase in FOXP3⁺‐expressing Tregs in an animal model for multiple sclerosis (MS). Interestingly, we detected a CD4⁺ T cell population with high PHB1 surface expression in blood samples from MS patients in comparison with age‐ and sex‐matched healthy subjects. Our observations suggest a pivotal role for the PHB‐CRAF‐MAPK signalling axis in regulating the polarization and pathogenicity of Th17 cells and unveil druggable targets in autoimmune disorders such as MS.

T辅助（Th）17细胞代表CD4 ⁺ T细胞的独特子集，对于清除包括细菌和真菌在内的细胞外病原体至关重要。但是，Th17细胞也参与协调自身免疫。通过采用定量的表面蛋白质组学，我们发现在进化上保守的禁止蛋白（PHB1 / 2）在鼠和人Th17细胞的表面都高度表达。细胞表面PHBs表达的增加有助于Th17细胞中CRAF / MAPK活化的增强。用配体（例如Vi多糖）（Typhim疫苗）靶向Th17细胞表面表达的PHB，可抑制CRAF-MAPK途径，降低白介素（IL）-17的表达，并改善病情，并增加FOXP3 ⁺在多发性硬化症（MS）动物模型中表达Treg。有趣的是，与年龄和性别相匹配的健康受试者相比，我们在MS患者的血液样本中检测到了具有高PHB1表面表达的CD4 ⁺ T细胞群体。我们的观察结果表明，PHB-CRAF-MAPK信号转导轴在调节Th17细胞的极化和致病性中起着关键作用，并揭示了自身免疫性疾病（例如MS）中的可药物治疗靶标。