Institute for Immunology, Biomedical Center, Faculty of Medicine, LMU Munich, Planegg-Martinsried 82152, Germany; and.
Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, LMU Munich, Planegg-Martinsried 82152, Germany.
J Immunol. 2020 Mar 1;204(5):1101-1110. doi: 10.4049/jimmunol.1900955.
Fingolimod is an effective treatment for relapsing-remitting multiple sclerosis. It is well established that fingolimod, a modulator of the sphingosine-1-phosphate pathway, restrains the egress of CCR7 lymphocytes from lymphatic tissues into the blood, thus resulting in reduced lymphocyte counts in peripheral blood. CXCR5 T follicular helper (Tfh) cells provide help to B cells, are essential for the generation of potent Ab responses, and have been shown to be critically involved in the pathogenesis of several autoimmune diseases. Besides lymphoid tissue-resident Tfh cells, CXCR5 circulating Tfh (cTfh) cells have been described in the blood, their numbers correlating with the magnitude of Tfh cells in lymphoid tissues. Although the effect of fingolimod on circulating lymphocyte subsets has been established, its effect on cTfh cells remains poorly understood. In this study, we found that although fingolimod strongly and disproportionally reduced cTfh cell frequencies, frequencies of activated cTfh cells were increased, and the composition of the cTfh cell pool was skewed toward a cTfh1 cell phenotype. The circulating T follicular regulatory cell subset and CXCR5 CD8 T cell frequencies were also strongly and disproportionally decreased after fingolimod treatment. In contrast, relative frequencies of CXCR5 memory Th cells as well as regulatory T and B cells were increased. In summary, these data provide new insights into fingolimod-induced compositional changes of lymphocyte populations in the blood, in particular cTfh cells, and thus contribute to a better understanding of the mechanism of action of fingolimod in multiple sclerosis patients.
芬戈莫德是治疗复发缓解型多发性硬化症的有效药物。已有充分证据表明，鞘氨醇-1-磷酸途径调节剂芬戈莫德可抑制 CCR7 淋巴细胞从淋巴组织迁出进入血液，从而导致外周血淋巴细胞计数减少。CXCR5 滤泡辅助性 T（Tfh）细胞为 B 细胞提供辅助作用，是产生有效 Ab 反应所必需的，并且已被证明在多种自身免疫性疾病的发病机制中起关键作用。除了淋巴组织驻留的 Tfh 细胞外，CXCR5 循环滤泡辅助性 T（cTfh）细胞也在血液中被描述，其数量与淋巴组织中 Tfh 细胞的数量相关。尽管已经确定了芬戈莫德对循环淋巴细胞亚群的影响，但对 cTfh 细胞的影响仍知之甚少。在这项研究中，我们发现尽管芬戈莫德强烈且不成比例地降低了 cTfh 细胞的频率，但激活的 cTfh 细胞的频率增加，并且 cTfh 细胞池的组成偏向于 cTfh1 细胞表型。循环 T 滤泡调节性细胞亚群和 CXCR5 CD8 T 细胞的频率在接受芬戈莫德治疗后也强烈且不成比例地降低。相比之下，CXCR5 记忆性 Th 细胞以及调节性 T 和 B 细胞的相对频率增加。总之，这些数据为芬戈莫德诱导血液中淋巴细胞群体的组成变化，特别是 cTfh 细胞，提供了新的见解，并有助于更好地理解芬戈莫德在多发性硬化症患者中的作用机制。
