Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome

Thymocytes and thymic epithelial cell (TEC) cross-talk is crucial to preserve thymic architecture and function, including maturation of TECs and dendritic cells, and induction of mechanisms of central tolerance.We have analyzed thymic maturation and organization in 9 infants with various genetic defects leading to complete or partial block in T-cell development. Profound abnormalities of TEC differentiation (with lack of AIRE expression) and severe reduction of thymic dendritic cells were identified in patients with Tnegative severe combined immunodeficiency, reticular dysgenesis, and Omenn syndrome. The latter also showed virtual absence of thymic Foxp3 T cells. In contrast, an IL2RG-R222C hypomorphic mutation
permissive for T-cell development allowed for TEC maturation, AIRE expression, and Foxp3 T cells. Our data provide
evidence that severe defects of thymopoiesis impinge on TEC homeostasis and may affect deletional and nondeletional
mechanisms of central tolerance, thus favoring immune dysreactive manifestations, as in Omenn syndrome.