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

[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 T -negative severe combined immunodeficiency , reticular dysgenesis , and Omenn syndrome . The latter also showed virtual absence of thymic Foxp 3 (+) T cells . In contrast , an IL 2 RG -R 222 C hypomorphic mutation permissive for T -cell development allowed for TEC maturation , AIRE expression , and Foxp 3 (+) 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 .