4.6 Article

Stabilized β-Catenin in Thymic Epithelial Cells Blocks Thymus Development and Function

期刊

JOURNAL OF IMMUNOLOGY
卷 182, 期 5, 页码 2997-3007

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AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0713723

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资金

  1. Swiss National Science Foundation [3100-61782.00, 3100-68310.02]
  2. European Community 6th Framework program Euro-Thymaide Integrated project [ROI-AI057477-01]
  3. National Institutes of Health
  4. Basel Cancer League
  5. National Health and Medical Research Council of Australia [CJ Martin Fellowship]

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Thymic T cell development is dependent on a specialized epithelial microenvironment mainly composed of cortical and medullary thymic epithelial cells (TECs). The molecular programs governing the differentiation and maintenance of TECs remain largely unknown. Wnt signaling is central to the development and maintenance of several organ systems but a specific role of this pathway for thymus organogenesis has not yet been ascertained. In this report, we demonstrate that activation or the canonical Writ signaling pathway by a stabilizing mutation of beta-catenin targeted exclusively to TECs changes the initial commitment of endodermal epithelia to a thymic cell fate. Consequently, the formation of a correctly composed and organized thymic microenvironment is prevented, thymic immigration of hematopoietic precursors is restricted, and intrathymic T cell differentiation is arrested at a very early developmental stage causing severe immunodeficiency. These results suggest that a precise regulation of canonical Wnt signaling in thymic epithelia is essential for normal thymus development and function. The Journal of Immunology, 2009, 182: 2997-3007.

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