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T cell-specific ablation of Fas leads to Fas ligand-mediated lymphocyte depletion and inflammatory pulmonary fibrosis.

Hao Z, Hampel B, Yagita H, Rajewsky K - J. Exp. Med. (2004)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: 620 University Ave., Toronto, ON, M5G 2C1, Canada. zyhao@uhnres.utoronto.ca

ABSTRACT
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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Leukocyte infiltration in the lungs and development of pulmonary fibrosis upon T cell–specific Fas inactivation. (a) Histological analysis of the lungs of mice at the age of 10 mo. H & E, hematoxylin and eosin staining; Ly-6G, staining for neutrophils (red); F4/80, staining for macrophages (blue); Elastic Stain, staining of elastic fibers (black blue) and cell nuclei (black). (b) Immunohistochemical staining of the lungs of 5–6-mo-old mice with anti-CD3 (red) and anti-CD19 (blue) antibody, and TUNEL (brown) on serial lung sections. (c) The staining was the same as in b, except the sections were from mice at the age of 15 mo. Three mice per group were analyzed, and representative results are shown. Bar, 100 μm.
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fig6: Leukocyte infiltration in the lungs and development of pulmonary fibrosis upon T cell–specific Fas inactivation. (a) Histological analysis of the lungs of mice at the age of 10 mo. H & E, hematoxylin and eosin staining; Ly-6G, staining for neutrophils (red); F4/80, staining for macrophages (blue); Elastic Stain, staining of elastic fibers (black blue) and cell nuclei (black). (b) Immunohistochemical staining of the lungs of 5–6-mo-old mice with anti-CD3 (red) and anti-CD19 (blue) antibody, and TUNEL (brown) on serial lung sections. (c) The staining was the same as in b, except the sections were from mice at the age of 15 mo. Three mice per group were analyzed, and representative results are shown. Bar, 100 μm.

Mentions: Accompanying T cell activation and the loss of lymphocytes, T cell–specific Fas KO mice developed a severe wasting syndrome after 10 mo (Fig. 5 a, mouse aged 15 mo). Compared with the controls, the mutant animals lost an average of ∼30% body weight, and 75% of the mutant animals died within 10–18 mo (Fig. 5 b and not depicted). Histological analysis of the lungs of 10-mo-old diseased mutants revealed severe pulmonary fibrosis as shown by massive accumulation of elastic fibers, and intense alveolitis with accumulation of inflammatory cells including lymphocytes, neutrophils, and activated macrophages in the lung parenchyma (Fig. 6 a). Mild to moderate cellular infiltrations were also seen in the liver and kidney, and occasionally in the pancreas and colon, but not in the heart and stomach of the animals (unpublished data). However, the lung disease was likely the main reason for the ultimate death of the animals.


T cell-specific ablation of Fas leads to Fas ligand-mediated lymphocyte depletion and inflammatory pulmonary fibrosis.

Hao Z, Hampel B, Yagita H, Rajewsky K - J. Exp. Med. (2004)

Leukocyte infiltration in the lungs and development of pulmonary fibrosis upon T cell–specific Fas inactivation. (a) Histological analysis of the lungs of mice at the age of 10 mo. H & E, hematoxylin and eosin staining; Ly-6G, staining for neutrophils (red); F4/80, staining for macrophages (blue); Elastic Stain, staining of elastic fibers (black blue) and cell nuclei (black). (b) Immunohistochemical staining of the lungs of 5–6-mo-old mice with anti-CD3 (red) and anti-CD19 (blue) antibody, and TUNEL (brown) on serial lung sections. (c) The staining was the same as in b, except the sections were from mice at the age of 15 mo. Three mice per group were analyzed, and representative results are shown. Bar, 100 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211818&req=5

fig6: Leukocyte infiltration in the lungs and development of pulmonary fibrosis upon T cell–specific Fas inactivation. (a) Histological analysis of the lungs of mice at the age of 10 mo. H & E, hematoxylin and eosin staining; Ly-6G, staining for neutrophils (red); F4/80, staining for macrophages (blue); Elastic Stain, staining of elastic fibers (black blue) and cell nuclei (black). (b) Immunohistochemical staining of the lungs of 5–6-mo-old mice with anti-CD3 (red) and anti-CD19 (blue) antibody, and TUNEL (brown) on serial lung sections. (c) The staining was the same as in b, except the sections were from mice at the age of 15 mo. Three mice per group were analyzed, and representative results are shown. Bar, 100 μm.
Mentions: Accompanying T cell activation and the loss of lymphocytes, T cell–specific Fas KO mice developed a severe wasting syndrome after 10 mo (Fig. 5 a, mouse aged 15 mo). Compared with the controls, the mutant animals lost an average of ∼30% body weight, and 75% of the mutant animals died within 10–18 mo (Fig. 5 b and not depicted). Histological analysis of the lungs of 10-mo-old diseased mutants revealed severe pulmonary fibrosis as shown by massive accumulation of elastic fibers, and intense alveolitis with accumulation of inflammatory cells including lymphocytes, neutrophils, and activated macrophages in the lung parenchyma (Fig. 6 a). Mild to moderate cellular infiltrations were also seen in the liver and kidney, and occasionally in the pancreas and colon, but not in the heart and stomach of the animals (unpublished data). However, the lung disease was likely the main reason for the ultimate death of the animals.

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: 620 University Ave., Toronto, ON, M5G 2C1, Canada. zyhao@uhnres.utoronto.ca

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus