Published online September 29, 2008
doi:10.1084/jem.20080134
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Hozumi et al.
Delta-like 4 is indispensable in thymic environment specific for T cell development
Katsuto Hozumi1,
Carolina Mailhos3,
Naoko Negishi1,
Ken-ichi Hirano1,
Takashi Yahata2,
Kiyoshi Ando2,
Saulius Zuklys4,
Georg A. Holländer4,
David T. Shima3, and
Sonoko Habu1
1 Department of Immunology and Research Center for Embryogenesis and Organogenesis, 2 Division of Hematopoiesis, Research Center for Regenerative Medicine, Tokai University School of Medicine, Isehara 259-1193, Japan
3 UCL Institute of Ophthalmology, Laboratory for Translational Vision Research, London EC1V 9EL, England, UK
4 Laboratory of Pediatric Immunology, Center for Biomedicine, Department of Clinical-Biological Sciences, University of Basel, 4058 Basel, Switzerland
CORRESPONDENCE Katsuto Hozumi: hozumi{at}is.icc.u-tokai.ac.jp
The thymic microenvironment is required for T cell development in vivo. However, in vitro studies have shown that when hematopoietic progenitors acquire Notch signaling via Delta-like (Dll)1 or Dll4, they differentiate into the T cell lineage in the absence of a thymic microenvironment. It is not clear, however, whether the thymus supports T cell development specifically by providing Notch signaling. To address this issue, we generated mice with a loxP-flanked allele of Dll4 and induced gene deletion specifically in thymic epithelial cells (TECs). In the thymus of mutant mice, the expression of Dll4 was abrogated on the epithelium, and the proportion of hematopoietic cells bearing the intracellular fragment of Notch1 (ICN1) was markedly decreased. Corresponding to this, CD4 CD8 double-positive or single-positive T cells were not detected in the thymus. Further analysis showed that the double-negative cell fraction was lacking T cell progenitors. The enforced expression of ICN1 in hematopoietic progenitors restored thymic T cell differentiation, even when the TECs were deficient in Dll4. These results indicate that the thymus-specific environment for determining T cell fate indispensably requires Dll4 expression to induce Notch signaling in the thymic immigrant cells.
© 2008 Hozumi et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
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