ZAP70 deficiency in humans is associated with abnormalities of thymic stromal cells: implications for T cell tolerance

Interaction between developing thymocytes and thymic stromal cells is essential to promote T lymphocyte development and maturation of thymic stromal cells, thereby permitting also negative selection of selfreactive T cells and generation of natural regulatory T (nTreg) cells. Here we provide the first detailed analysis of thymic architecture and stromal cell composition in patients with ZAP70 deficiency. We demonstrate that ZAP70 deficiency in humans is permissive for the generation of cortical and medullary thymic epithelial cells, for the expression of AIRE and for the development of nTreg cells. However, the number of AIRE+ cells and of FOXP3+ cells is significantly reduced as compared to normal thymus. Furthermore, the thymus of ZAP70-deficient patients shows impaired maturation of medullary thymic epithelial cells and depletion of all major dendritic cell subtypes. These abnormalities may account for the occurrence of Omenn syndrome and other manifestations of immune dysregulation in patients with ZAP70 deficiency. At the same time, abnormalities of thymic architecture and stromal cell maturation in patients with ZAP70 deficiency are milder than in earlier defects in T cell development, thereby accounting for the lower frequency of Omenn syndrome and of autoimmune complications in ZAP70 deficiency than in other conditions, such as RAG deficiency