Submitted March 16, 2009
Accepted April 24, 2009
Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome
Pietro Luigi Poliani, Fabio Facchetti, Maria Ravanini, Andrew Richard Gennery, Anna Villa, Chaim M. Roifman, and Luigi D. Notarangelo*
Department of Pathology, University of Brescia, Brescia, Italy
Department of Paediatric Immunology, Newcastle upon Tyne Hospitals Foundation Trust, Newcastle upon Tyne, United Kingdom
TIGET- H. San Raffaele, Milano, Italy
Hospital for Sick Children, Toronto, Canada
Division of Immunology, Children's Hospital, Boston, MA, United States
* Corresponding author; email: luigi.notarangelo{at}childrens.harvard.edu.
Thymocytes and thymic epithelial cells (TECs) cross-talk is crucial to preserve thymic architecture and function, including maturation of TECs and dendritic cells (DCs), and induction of mechanisms of central tolerance. We have analyzed thymic maturation and organization in nine infants with various genetic defects leading to complete or partial block in T-cell development. Profound abnormalities of TECs differentiation (with lack of AIRE expression) and severe reduction of thymic DCs were identified in patients with T-negative SCID, reticular dysgenesis and Omenn syndrome (OS). 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 non-deletional mechanisms of central tolerance, thus favoring immune dysreactive manifestations, as in OS.
