Clonal Analysis of Regulatory T Cell Defect in Patients with Autoimmune Polyendocrine Syndrome Type 1 Suggests Intrathymic Impairment

Mutations in the Autoimmune Regulator (AIRE) gene disrupt thymic T cell development and negative selection, leading to the recessively inherited polyendocrine autoimmune disease APS-1 (autoimmune polyendocrine syndrome type 1). The patients also have a functional defect in the FOXP3+ regulatory T cell population, but its origin is unclear. Here we have used T cell receptor sequencing to analyze the clonal relationship of major CD4+ T cell subsets in 3 patients and 3 healthy controls. The naive regulatory T cells showed little overlap with helper T cell subsets, supporting divergence in the thymus. The activated/memory regulatory T cell subset displayed more sharing with helper T cells, but was mainly recruited from the naive regulatory T cell population. These clonal patterns were very similar in both patients and controls. However, naive regulatory T cells isolated from the patients had a significantly longer T cell receptor complementarity determining region 3 than any other population, suggesting failure of thymic selection. These data indicate that the peripheral differentiation of regulatory T cells in APS-1 patients is not different from that in healthy controls. Rather, the patients’ naive regulatory T cells may have an intrinsic defect imprinted already in the thymus. This article is protected by copyright. All rights reserved.