Dysregulated proinflammatory circulating follicular helper T cells and suppressive follicular regulatory T cells in patients with multiple sclerosis

Follicular T helper (Tfh) and regulatory (Tfreg) cells are distinct subsets of CD4+T lymphocytes, regulating humoral immune responses in the germinal center. Dysregulated Tfh and Tfreg cells are believed to associate with autoimmunity. Here, we evaluated the frequencies of circulating CXCR5+PD-1+ Tfh (cTfh) and CXCR5+PD-1+FoxP3+CD25+ Tfreg (cTfreg) cells, and their corresponding cytokines from the peripheral blood mononuclear cells of 20 patients with relapsing-remitting multiple sclerosis (MS) and 12 age- and sex-matched healthy controls (HC). Subsets of cTfh cells by Th1 and Th17 related surface markers (CXCR3 and CCR6) were also evaluated. We found the frequency of cTfh cells was significantly higher in MS patients compared to HC (p=0.002). Conversely, cTfreg cells were downregulated in MS patients (p<0.0001). IL-21 producing cTfh cells were significantly increased in MS patients (p=0.003), while IL-10 secreting cTfreg cells were decreased in MS compared to HC (p=0.02). Among cTfh cells, cTfh17.1 cells were major subtypes that were significantly increased in MS compared to HC (p=0.002) and the frequency of IL-21 secreting cells were highest. These results suggest that an imbalanced distribution of cTfh and cTfreg exist in MS, which contributes to reciprocally altered IL-21 and IL-10 production.