Inversion of the Vδ1 to Vδ2 γδ T cell ratio in CVID is not restored by IVIg and is associated with immune activation and exhaustion

Common variable immunodeficiency (CVID) is defined by low levels of IgG and IgA, but perturbations in T cells are also commonly found. However, there is limited information on gamma delta T cells in CVID patients. Newly diagnosed CVID patients (n=15) were enrolled before and after intravenous IgG (IVIg) replacement therapy. Cryopreserved peripheral blood mononuclear cells were then used to study gamma delta T cells and CVID patients were compared to healthy controls (n=22). The frequency and absolute count of V delta 1 gamma delta T cells was found to be increased in CVID (median 0.60% vs 2.64%, P<0.01 and 7.5 vs 39, P<0.01 respectively), while they were decreased for V delta 2 gamma delta T cells (median, 2.36% vs 0.74%, P<0.01 and 37.8 vs 13.9, P<0.01 respectively) resulting in an inversion of the V delta 1 to V delta 2 ratio (0.24 vs 1.4, P<0.001). Markers of immune activation were elevated on all subsets of gamma delta T cells, and HLA-DR expression was associated with an expansion of V delta 1 gamma delta T cells (r=0.73, P=0.003). Elevated PD-1 expression was found only on V delta 2 gamma delta T cells (median 1.15% vs 3.08%, P<0.001) and was associated with the decrease of V delta 2 gamma delta T cells (r=-0.67, P=0.007). IVIg had no effect on the frequency of V delta 1 and V delta 2 gamma delta T cells or HLA-DR expression, but alleviated CD38 expression on V delta 1 gamma delta T cells (median MFI 965 vs 736, P<0.05). These findings suggest that immunological perturbations of gamma delta T cells are a general feature associated with CVID and are only partially reversed by IVIg therapy.