To study the role of Fas–Fas ligand (FasL) interaction-mediated apoptosis in lymphocyte homeostasis, we generated a mutant fas allele allowing conditional inactivation of the fas gene through Cre-mediated recombination. Experiments in which Fas was ablated in T cells, B cells, T and B cells, or in a more generalized manner demonstrated that the development of lymphoproliferative disease as seen in Fas-deficient mice requires Fas ablation in lymphoid and nonlymphoid tissues. Selective inactivation of Fas in T cells led to a severe lymphopenia over time, accompanied by up-regulation of FasL on activated T cells and apoptosis of peripheral lymphocytes. In addition, the mutant animals developed a fatal wasting syndrome caused by massive leukocyte infiltration in the lungs together with increased inflammatory cytokine production and pulmonary fibrosis. Inhibition of Fas–FasL interaction in vivo completely prevented the loss of lymphocytes and initial lymphocyte infiltration in the lungs. Thus, FasL-mediated interaction of activated, Fas-deficient T cells with Fas-expressing cells in their environment leads to break down of lymphocyte homeostasis and development of a lung disease strikingly resembling idiopathic pulmonary fibrosis in humans, a common and severe disease for which the mutant mice may serve as a first animal model.
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17 May 2004
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May 17 2004
T Cell–specific Ablation of Fas Leads to Fas Ligand–mediated Lymphocyte Depletion and Inflammatory Pulmonary Fibrosis
Zhenyue Hao,
Zhenyue Hao
1Institute for Genetics, University of Cologne, D-50931 Cologne, Germany
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Brigitte Hampel,
Brigitte Hampel
1Institute for Genetics, University of Cologne, D-50931 Cologne, Germany
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Hideo Yagita,
Hideo Yagita
3Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
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Klaus Rajewsky
Klaus Rajewsky
1Institute for Genetics, University of Cologne, D-50931 Cologne, Germany
2The CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115
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Zhenyue Hao
1Institute for Genetics, University of Cologne, D-50931 Cologne, Germany
Brigitte Hampel
1Institute for Genetics, University of Cologne, D-50931 Cologne, Germany
Hideo Yagita
3Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
Klaus Rajewsky
1Institute for Genetics, University of Cologne, D-50931 Cologne, Germany
2The CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115
Address correspondence to Zhenyue Hao at his present address Advanced Medical Discovery Institute, 620 University Ave., Toronto, ON, M5G 2C1, Canada. Phone: (416) 946-4501; Fax: (416) 204-2278; email: [email protected]; or Klaus Rajewsky, The CBR Institute for Biomedical Research, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115. Phone: (617) 278-3132; Fax: (617) 278-3129; email: [email protected]
Abbreviations used in this paper: ALPS, autoimmune lymphoproliferative syndrome; BALF, bronchoalveolar lavage fluid; DN, double negative; FasL, Fas ligand; IPF, idiopathic pulmonary fibrosis; MIP-2, macrophage inflammatory protein 2.
Received:
December 18 2003
Accepted:
April 01 2004
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2004
J Exp Med (2004) 199 (10): 1355–1365.
Article history
Received:
December 18 2003
Accepted:
April 01 2004
Citation
Zhenyue Hao, Brigitte Hampel, Hideo Yagita, Klaus Rajewsky; T Cell–specific Ablation of Fas Leads to Fas Ligand–mediated Lymphocyte Depletion and Inflammatory Pulmonary Fibrosis . J Exp Med 17 May 2004; 199 (10): 1355–1365. doi: https://doi.org/10.1084/jem.20032196
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