Early Defects in Human T-cell Development Severely Affect Distribution and Maturation of Thymic Stromal Cells: Possible Implications for the Pathophysiology of Omenn Syndrome

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2009 May 6

PMID 19414857

Citations 72

Authors

Pietro Luigi Poliani

Fabio Facchetti

Maria Ravanini

Andrew Richard Gennery

Anna Villa

Chaim M Roifman

Luigi D Notarangelo

Affiliations

Soon will be listed here.

Abstract

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 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.

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