(TCRαβ+) Double-Negative T Cells in Type 1 Diabetes Mellitus.

Type 1 Diabetes Mellitus (T1DM) is an autoimmune disease characterized by the destruction of pancreatic β-cells. Both lymphocytes and various innate immune cells contribute to its immunopathogenesis. Among lymphocytes, in addition to CD8+ T cells, CD4+ T cells, and B cells, growing attention has been directed toward some unconventional T-cell subsets, such as TCRαβ+ double-negative T (DNT) cells, based on findings in several autoimmune/rheumatic diseases. This narrative review aims to summarize and analyze the available data on the potential role of DNT cells (and, in detail, the TCRαβ+ subset) in the immunopathogenesis of autoimmune diabetes/T1DM. Most of the current knowledge regarding DNT cell homeostasis in this pathological setting derives from experimental models, especially Non-Obese Diabetic (NOD) mice. In murine autoimmune diabetes, TCRαβ+DNT cells appear to exert a predominantly protective role against immune-mediated β-cell injury. These cells can be observed in multiple anatomical sites, including the thymus, peripheral blood, secondary lymphoid organs (spleen and lymph nodes) and, under pathological conditions, in non-lymphoid organs, like within the pancreas and, in detail, pancreatic islets, in the setting of autoimmune diabetes. Experimental evidence suggests that TCRαβ+DNT cells may attenuate the CD8+ T cell-mediated destruction of pancreatic β-cells, both directly and indirectly, through the inhibition of CD4+ T cells and B cells implicated in this immunopathological process. Unfortunately, very few studies have examined TCRαβ+DNT cells in patients with T1DM. This important knowledge gap highlights the need for dedicated clinical and translational research to better elucidate the role of TCRαβ+DNT cells in T1DM, especially given the preliminary findings pointing toward their potential immunoregulatory relevance.