Association of Decreased Percentage of Vδ2+Vγ9+ γδ T Cells With Disease Severity in Multiple Sclerosis

We recently reported that deletion-type copy number variations of the T cell receptor (TCR)gamma, alpha, and delta genes greatly enhanced susceptibility to multiple sclerosis (MS). However, the effect of abnormal TCR gamma delta gene rearrangement on MS pathogenesis remains unknown. In the present study, we aimed to clarify gamma delta 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 V delta 2(+) and V delta 2(+) V gamma 9(+) cells in gamma delta T cells (p(corr) = 0.0297 and p(corr) = 0.0288, respectively) and elevated V delta 1/ V delta 2 ratios compared with HCs (p = 0.0033). The percentages of interferon (IFN)-gamma V+delta 2(+) and interleukin (IL)-17A(+)IFN-gamma(+) V delta 2(+) cells in gamma delta T cells, as well as IFN-gamma(+) cells in V delta 2(+) gamma delta T cells, were significantly lower in MS patients than in HCs (p(corr) < 0.0009, p(corr) = 0.0135, and p(corr) = 0.0054, respectively). The percentages of V delta 2(+) and V delta 2(+) V gamma 9(+) cells in gamma delta 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 V delta 2(+) and V delta 2(+) V gamma 9(+) cells of total CD3(+) T cells had strong positive correlations with the percentage of CD25(+)CD127(low/-) 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 V delta 2(+)V gamma 9(+) gamma delta T cells are associated with disability in MS. Therefore, the V delta 1/V delta 2 ratio might be a candidate biomarker for predicting disease severity in MS.