T1D progression is associated with loss of CD3⁺CD56⁺ regulatory T cells that control CD8⁺ T cell effector functions

An unresolved issue in autoimmunity is the lack of surrogate biomarkers of immunological self-tolerance for disease monitoring. Here, we show that peripheral frequency of a regulatory T cell population, characterized by the co-expression of CD3 and CD56 molecules (T_R3-56), is reduced in subjects with new-onset type 1 diabetes (T1D). In three independent T1D cohorts, we find that low frequency of circulating T_R3-56 cells is associated with reduced β-cell function and with the presence of diabetic ketoacidosis. As autoreactive CD8⁺ T cells mediate disruption of insulin-producing β-cells^1-3, we demonstrate that T_R3-56 cells can suppress CD8⁺ T cell functions in vitro by reducing levels of intracellular reactive oxygen species. The suppressive function, phenotype and transcriptional signature of T_R3-56 cells are also altered in T1D children. Together, our findings indicate that T_R3-56 cells constitute a regulatory cell population that controls CD8⁺ effector functions, whose peripheral frequency may represent a traceable biomarker for monitoring immunological self-tolerance in T1D.