The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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Published 17 May 2004. doi:10.1084/jem.20032196
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 10, 1355-1365
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T Cell–specific Ablation of Fas Leads to Fas Ligand–mediated Lymphocyte Depletion and Inflammatory Pulmonary Fibrosis

Zhenyue Hao1, Brigitte Hampel1, Hideo Yagita3, and Klaus Rajewsky1,2

1 Institute for Genetics, University of Cologne, D-50931 Cologne, Germany
2 The CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115
3 Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan

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: zyhao{at}uhnres.utoronto.ca; 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: rajewsky{at}cbr.med.harvard.edu

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.

Key Words: lymphocyte homeostasis • lymphopenia • apoptosis • lungs • conditional gene targeting

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.


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