Abstract
We recently reported that deletion-type copy number variations of the T cell receptor (TCR) γ, α, and δ genes greatly enhanced susceptibility to multiple sclerosis (MS). However, the effect of abnormal TCR γδ gene rearrangement on MS pathogenesis remains unknown. In the present study, we aimed to clarify γδ TCR repertoire alterations and their relationship to clinical and immunological parameters in MS patients by comprehensive flow cytometric immunophenotyping. Peripheral blood mononuclear cells obtained from 30 untreated MS patients in remission and 23 age- and sex-matched healthy controls (HCs) were stained for surface markers and intracellular cytokines after stimulation with phorbol 12-myristate 13-acetate and ionomycin, and analyzed by flow cytometry. MS patients showed significantly decreased percentages of Vδ2+ and Vδ2+Vγ9+ cells in γδ T cells (pcorr = 0.0297 and pcorr = 0.0288, respectively) and elevated Vδ1/Vδ2 ratios compared with HCs (p = 0.0033). The percentages of interferon (IFN)-γ+Vδ2+ and interleukin (IL)-17A+IFN-γ+Vδ2+ cells in γδ T cells, as well as IFN-γ+ cells in Vδ2+ γδ T cells, were significantly lower in MS patients than in HCs (pcorr < 0.0009, pcorr = 0.0135, and pcorr = 0.0054, respectively). The percentages of Vδ2+ and Vδ2+Vγ9+ cells in γδ T cells were negatively correlated with both the Expanded Disability Status Scale score (r = −0.5006, p = 0.0048; and r = −0.5040, p = 0.0045, respectively) and Multiple Sclerosis Severity Score (r = –0.4682, p = 0.0091; and r = –0.4706, p = 0.0087, respectively), but not with age at disease onset, disease duration, or annualized relapse rate. In HCs, the percentages of Vδ2+ and Vδ2+Vγ9+ cells of total CD3+ T cells had strong positive correlations with the percentage of CD25+CD127low/− cells in CD4+ T cells (r = 0.7826, p < 0.0001; and r = 0.7848, p < 0.0001, respectively), whereas such correlations were totally absent in MS patients. These findings suggest that decreased Vδ2+Vγ9+ γδ T cells are associated with disability in MS. Therefore, the Vδ1/Vδ2 ratio might be a candidate biomarker for predicting disease severity in MS.
Highlights
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) mediated by auto reactive T cells [1]
The per centages of Vδ2+ and Vδ2+Vγ9+ γδ T cells in CD3+ T cells were significantly reduced in MS patients compared with healthy controls (HCs), even after Bonferroni–Dunn’s correction
We considered a decrease of Vδ2+ T cells to be a primary change, because the decrease of Vδ2+ T cells but not increase of Vδ1+ T cells was significant even after Bonferroni–Dunn’s correction to minimize statistical error
Summary
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) mediated by auto reactive T cells [1]. In MS, Th1 and Th17 cells are increased at relapse in peripheral blood and suppressed by IFN-β treatment [4]. These observations collectively suggest the involvement of Th1/Th17 cells in relapse induction. The percentage of Th1/Th17 cells in peripheral blood has no or a poor correlation with MS severity. Surrogate immuno logical markers for disease severity present in peripheral blood remain to be established in MS
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