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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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Defective Fas expression in nonlymphoid cells is required for the development of lymphoproliferative disease. FACS® analysis of DN T cells in LNs is shown. (a) 7–9-mo-old C57BL/6 mice with Fas deletion in tissue-specific or inducible manner. Mx–cre-mediated deletion was induced 8 mo before analysis. (b) Mild lymphadenopathy and splenomegaly upon T, B, and T plus B cell–specific Fas inactivation in (C57BL/6×MRL) F1 mice at the age of 5–6 mo. Pictures of spleen and LNs are shown. Weights are shown as means ± SD (n = 2∼6). Cell numbers shown on top of FACS® plots indicate total cellularity from the largest LNs of mice suffering from lymphadenopathy or of inguinal or cervical LNs of mice without apparent lymphadenopathy.
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fig2: Defective Fas expression in nonlymphoid cells is required for the development of lymphoproliferative disease. FACS® analysis of DN T cells in LNs is shown. (a) 7–9-mo-old C57BL/6 mice with Fas deletion in tissue-specific or inducible manner. Mx–cre-mediated deletion was induced 8 mo before analysis. (b) Mild lymphadenopathy and splenomegaly upon T, B, and T plus B cell–specific Fas inactivation in (C57BL/6×MRL) F1 mice at the age of 5–6 mo. Pictures of spleen and LNs are shown. Weights are shown as means ± SD (n = 2∼6). Cell numbers shown on top of FACS® plots indicate total cellularity from the largest LNs of mice suffering from lymphadenopathy or of inguinal or cervical LNs of mice without apparent lymphadenopathy.

Mentions: Splenomegaly and lymphadenopathy were evident in fasdel/del C57BL/6 mice when they became older than 5 mo. In contrast, there was no evidence for lymphoproliferative disease in 7–9-mo-old mice lacking Fas on T, B, or both T and B lymphocytes (Fig. 2 a). In the LNs of these animals, there were almost no DN (i.e., Thy1+B220+CD4−CD8−) T cells, they are typically seen in mice homozygous for the lpr mutation. With respect to autoantibody formation, T or B cell–specific deletion of Fas led to a three- to eightfold increase of IgM and IgG antibodies specific for single-stranded DNA, but this was still two- to threefold below the titers seen in fasdel/del mice (unpublished data). Thus, Fas inactivation in lymphocytes only is insufficient for the lpr disease to occur, indicating that Fas-defective nonlymphoid cell types are also critically involved in disease development. To prove this point, inactivation of Fas in multiple cell types, including lymphocytes and nonhematopoietic cells such as liver cells, was induced in fasfl/fl, Mx-cre mice by injection of Poly(I) · Poly(C) (22). As expected, mice with Fas inactivation in both lymphoid and nonlymphoid cells reconstituted the lymphoproliferative disease seen in fasdel/del mice (Fig. 2 a).


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)

Defective Fas expression in nonlymphoid cells is required for the development of lymphoproliferative disease. FACS® analysis of DN T cells in LNs is shown. (a) 7–9-mo-old C57BL/6 mice with Fas deletion in tissue-specific or inducible manner. Mx–cre-mediated deletion was induced 8 mo before analysis. (b) Mild lymphadenopathy and splenomegaly upon T, B, and T plus B cell–specific Fas inactivation in (C57BL/6×MRL) F1 mice at the age of 5–6 mo. Pictures of spleen and LNs are shown. Weights are shown as means ± SD (n = 2∼6). Cell numbers shown on top of FACS® plots indicate total cellularity from the largest LNs of mice suffering from lymphadenopathy or of inguinal or cervical LNs of mice without apparent lymphadenopathy.
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Related In: Results  -  Collection

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

fig2: Defective Fas expression in nonlymphoid cells is required for the development of lymphoproliferative disease. FACS® analysis of DN T cells in LNs is shown. (a) 7–9-mo-old C57BL/6 mice with Fas deletion in tissue-specific or inducible manner. Mx–cre-mediated deletion was induced 8 mo before analysis. (b) Mild lymphadenopathy and splenomegaly upon T, B, and T plus B cell–specific Fas inactivation in (C57BL/6×MRL) F1 mice at the age of 5–6 mo. Pictures of spleen and LNs are shown. Weights are shown as means ± SD (n = 2∼6). Cell numbers shown on top of FACS® plots indicate total cellularity from the largest LNs of mice suffering from lymphadenopathy or of inguinal or cervical LNs of mice without apparent lymphadenopathy.
Mentions: Splenomegaly and lymphadenopathy were evident in fasdel/del C57BL/6 mice when they became older than 5 mo. In contrast, there was no evidence for lymphoproliferative disease in 7–9-mo-old mice lacking Fas on T, B, or both T and B lymphocytes (Fig. 2 a). In the LNs of these animals, there were almost no DN (i.e., Thy1+B220+CD4−CD8−) T cells, they are typically seen in mice homozygous for the lpr mutation. With respect to autoantibody formation, T or B cell–specific deletion of Fas led to a three- to eightfold increase of IgM and IgG antibodies specific for single-stranded DNA, but this was still two- to threefold below the titers seen in fasdel/del mice (unpublished data). Thus, Fas inactivation in lymphocytes only is insufficient for the lpr disease to occur, indicating that Fas-defective nonlymphoid cell types are also critically involved in disease development. To prove this point, inactivation of Fas in multiple cell types, including lymphocytes and nonhematopoietic cells such as liver cells, was induced in fasfl/fl, Mx-cre mice by injection of Poly(I) · Poly(C) (22). As expected, mice with Fas inactivation in both lymphoid and nonlymphoid cells reconstituted the lymphoproliferative disease seen in fasdel/del mice (Fig. 2 a).

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