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Background  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. 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.    Methods  Comprehensive 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).    Results  The 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).    Conclusions  The 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.    Electronic supplementary material  The online version of this article (10.1186/s12974-019-1574-5) contains supplementary material, which is available to authorized users.

Long-term use of interferon-β in multiple sclerosis increases Vδ1−Vδ2−Vγ9− γδ T cells that are associated with a better outcome