Abstract
BackgroundWe previously reported that Vδ2+Vγ9+ γδ T cells were significantly decreased in multiple sclerosis (MS) patients without disease-modifying therapies (untreated MS) and were negatively correlated with Expanded Disability Status Scale (EDSS) scores, suggesting protective roles of Vδ2+Vγ9+ γδ T cells. Interferon-β (IFN-β) is one of the first-line disease-modifying drugs for MS. However, no previous studies have reported changes in γδ T cell subsets under IFN-β treatment. Therefore, we aimed to clarify the effects of the long-term usage of IFN-β on γδ T cell subsets in MS patients.MethodsComprehensive flow cytometric immunophenotyping was performed in 35 untreated MS and 21 MS patients on IFN-β for more than 2 years (IFN-β-treated MS) including eight super-responders fulfilling no evidence of disease activity criteria, and 44 healthy controls (HCs).ResultsThe percentages of Vδ2+Vγ9+ cells in γδ T cells were significantly lower in untreated and IFN-β-treated MS patients than in HCs. By contrast, the percentages of Vδ1−Vδ2−Vγ9− cells in γδ T cells were markedly higher in IFN-β-treated MS patients than in HCs and untreated MS patients (both p < 0.001). A significant negative correlation between the percentages of Vδ2+Vγ9+ cells in γδ T cells and EDSS scores was confirmed in untreated MS but not evident in IFN-β-treated MS. Moreover, class-switched memory B cells were decreased in IFN-β-treated MS compared with HCs (p < 0.001) and untreated MS patients (p = 0.006). Interestingly, the percentages of Vδ1−Vδ2−Vγ9− cells in γδ T cells were negatively correlated with class-switched memory B cell percentages in all MS patients (r = − 0.369, p = 0.005), and the percentages of Vδ1−Vδ2−Vγ9− cells in Vδ1−Vδ2− γδ T cells were negatively correlated with EDSS scores only in IFN-β super-responders (r = − 0.976, p < 0.001).ConclusionsThe present study suggests that long-term usage of IFN-β increases Vδ1−Vδ2−Vγ9− γδ T cells, which are associated with a better outcome, especially in IFN-β super-responders. Thus, increased Vδ1−Vδ2−Vγ9− cells together with decreased class-switched memory B cells may contribute to the suppression of disease activity in MS patients under IFN-β treatment.
Highlights
We previously reported that Vδ2+Vγ9+ γδ T cells were significantly decreased in multiple sclerosis (MS) patients without disease-modifying therapies and were negatively correlated with Expanded Disability Status Scale (EDSS) scores, suggesting protective roles of Vδ2+Vγ9+ γδ T cells
Association between B cell subsets and disease severity in MS patients treated by IFN-β When we examined the association between B cell subsets and disease severity, the percentages of memory B cells and class-switched memory B cells were positively associated with EDSS scores only in the evidence of disease activity’ (EDA) group of IFN-β-treated MS patients (r = 0.722, p = 0.005; r = 0.719, p = 0.006, respectively), but not in the no-evidence of disease activity’ (NEDA) group (p = 0.601 and 0.518, respectively) (Fig. 4)
Extensive flow cytometric immunophenotyping of peripheral blood lymphocytes from untreated and persistently IFN-β-treated MS patients revealed that the long-term usage of IFN-β increased the percentages of Vδ1−Vδ2−Vγ9− γδ T cells and decreased the percentages of class-switched memory B cells without a major influence on other T and B lymphocyte subsets, which may contribute to the attenuation of disease activity
Summary
We previously reported that Vδ2+Vγ9+ γδ T cells were significantly decreased in multiple sclerosis (MS) patients without disease-modifying therapies (untreated MS) and were negatively correlated with Expanded Disability Status Scale (EDSS) scores, suggesting protective roles of Vδ2+Vγ9+ γδ T cells. A deletion-type CNV at the TCRα locus covers TCRδ genes [3]. Based on these facts, we hypothesized that a deviation in TCRγδ gene rearrangement contributes to the pathogenesis of MS. We conducted comprehensive flow cytometric immunophenotyping in MS patients without disease-modifying therapies (DMTs) (defined as untreated MS), and reported that percentages of Vδ2+ and Vδ2+Vγ9+ cells in γδ T cells were decreased and that the Vδ1/Vδ2 ratio was increased compared with healthy controls (HCs) [10]. Vδ2+Vγ9+ γδ T cells showed a negative correlation with disability and a positive correlation with the percentages of Treg in CD4+ T cells, suggesting the protective roles of Vδ2+Vγ9+ γδ T cells
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