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

Abstract

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.

γδ T Cells in Brain Homeostasis and Diseases

“…On the other hand, Vδ2 + T cells have strong cytotoxicity against oligodendrocytes ( 98 ). Under MS, long-term treatment of IFN-β expands Vδ1 - Vδ2 - Vγ9 - γδ T cells, which were related to better outcome of MS patients ( 99 ). Taken together, human data also suggested a heterogenous role of γδ T cells in the MS progression.…”

Choroid plexus epithelium and its role in neurological diseases

“…The beneficial effect of interferon-β (IFNβ) is thought to stem from its change in the environment from inflammatory regulation to regulation at several levels of immune cell activation, while preventing immune cell migration through the blood-brain barrier to the central nervous system. The pleiotropic effects of IFN-β on the peripheral immune system mainly include the reduction of pathogenic Th1 and Th17 cells and the increase of IL-10-producing Tregs via the JAK-STAT signaling pathway (Furber et al, 2017;Maimaitijiang et al, 2019;Ayatollahi et al, 2020). In addition, IFN-β reduces CD27 + memory B cells and increases IL-10-producing B cells, and IFN-β may downregulate the ability of adhesion molecules to inhibit pro-inflammatory cell entry into the CNS.…”

B Cells in Neuroinflammation: New Perspectives and Mechanistic Insights

“…A role for T cells in the generation of EAE pathology was further demonstrated through the adoptive transfer of myelin-specific T cells that were able to induce EAE [ 69 ]. These studies guided the field to the development of many of the therapies that are currently available, in particular interferon ß [ 70 , 71 ]. A potential challenge with the murine EAE models is the influence of species specificity, and to begin addressing these concerns a non-human primate model was developed in the marmoset.…”