The temporal association between γδ t cells and the natural history of insulin-dependent diabetes

We previously reported a significant increase in percentages of peripheral blood γδ+ T cells in islet cell antibody (ICA) positive relatives of patients with insulin-dependent diabetes (IDD). In the present study, we further characterized this T cell abnormality in a larger group of ICA+ subjects and report that (1) Percentages of γδ+ T lymphocytes were significantly increased only in subjects with high ICA titers (≥ 20 JDF units) (P = 0.005) and resulted from an increase in absolute numbers of γδ+ T lymphocytes. (2) In these subjects, the increase in γδ+ T lymphocytes was associated with an increase in the Vγ₉, Vδ₂ subpopulation (r = 0.99). (3) In these same subjects, high percentages of γδ+ T lymphocytes were associated with normal β cell function while low percentages were associated with diminished insulin response. Using 65 μU/ml as the threshold of abnormal intravenous glucose tolerance test (IVGTT) response, percentages of γδ+ T lymphocytes could significantly predict IVGTT status in these subjects (P < 0.01). A longitudinal follow-up further suggested that the development of an abnormal IVGTT response and progression to diabetes was associated with a decrease in percentages of γδ+ T lymphocytes while patients whose γδ+ T cell percentages remained high retained normal β cell function. Our data therefore suggest that γδ+ T lymphocytes and more specifically Vγ₉, Vδ₂ T cells are implicated in the autoimmune process leading to diabetes and may have a regulatory role. The monitoring of their percentages in the blood of patients at risk for diabetes may be useful as an additional predictor of diabetes development.