Absence of PD-1 expression on T_FH and T_FC cell subsets correlates with severity of multiple sclerosis

Follicular CD4⁺ T (T_FH) cells have been implicated in the pathogenesis of multiple sclerosis (MS). However, studies evaluating follicular CD8⁺ T (T_FC) cells and the relationship between T_FH/T_FC cells with clinical MS parameters are lacking. Here, the frequency of circulating T_FH/T_FC cells from healthy and MS subjects was determined by cytometry according the expression of PD-1, CXCR3, CCR6, IL-21, IFN-γ and IL-17 by CXCR5⁺CD4⁺/CD8⁺T-cells. The plasma CXCL13 and NfL levels were quantified by ELISA. The degree of neurological disability and brain lesions were determined by EDSS score and magnetic resonance imaging, respectively. Relapse occurrence was evaluated during 1-year follow-up. Our results demonstrated that PD-1⁺IL-21⁺T_FH-cell subsets (T_FH1, T_FH17.1 and T_FH17) frequency and the percentage of PD-1⁺IL-21⁺T_FC17.1 and PD-1^-IL-21⁺T_FH17.1/T_FC17.1 cells were higher in the MS than in the control group. Different IL-17-expressing PD-1^-IL-21⁺T_FH/T_FC cell subsets positively correlated with plasma CXCL13 and NfL levels. Also, circulating PD-1^-IL-21⁺T_FH17/T_FC17 directly correlated with neurological disabilities. While radiological activity of disease positively correlated with percentage of PD-1^-IL-21⁺T_FH17.1/T_FH17 cells and PD-1^-IL-21⁺T_FC1/T_FC17.1/T_FC17 cells, clinical activity of MS was associated with both elevated levels of CXCL13 and NfL and the frequencies of PD-1^-IL-21⁺T_FH17.1/T_FH17 and PD-1^-IL-21⁺T_FC1/T_FC17.1 cells. In summary, our findings suggest that PD-1^-T_FH/T_FC cells able to produce IL-21, IFN-γ and IL-17 could be a signature of MS severity.