FAS/FAS-L dependent killing of activated human monocytes and macrophages by CD4+CD25− responder T cells, but not CD4+CD25+ regulatory T cells

Jagger, Ann; Evans, Hayley G.; Walter, Gina; Gullick, Nicola; Menon, Bina; Ballantine, L.; Gracie, Alastair; Magérus-Chatinet, Aude; Tiemessen, Machteld M.; Geissmann, Frédéric; Rieux-Laucat, Frédéric; Taams, Leonie S.

doi:10.1016/j.jaut.2011.11.015

Cited by 24 publications

(32 citation statements)

References 54 publications

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“…Similarly, although FasL can be expressed by most T-lymphocyte subsets (7,18,22,52), evidence of a direct link to macrophage apoptosis in vivo is lacking. For instance, CD4 ϩ T lymphocytes can be programmed to express FasL to induce apoptosis of macrophages in culture (1,20,22,38,42) but induction of macrophage apoptosis by FasL-expressing CD4 ϩ T lymphocytes in vivo is not described. The regulatory subset of CD4 ϩ T lymphocytes (CD4 ϩ CD25 ϩ ) can express FasL, but they do not directly induce monocyte/macrophage apoptosis through Fas (22).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, CD4 ϩ T lymphocytes can be programmed to express FasL to induce apoptosis of macrophages in culture (1,20,22,38,42) but induction of macrophage apoptosis by FasL-expressing CD4 ϩ T lymphocytes in vivo is not described. The regulatory subset of CD4 ϩ T lymphocytes (CD4 ϩ CD25 ϩ ) can express FasL, but they do not directly induce monocyte/macrophage apoptosis through Fas (22). Rather, it is thought that they render macrophages susceptible to cell death by altering macrophage activation and programming (22,49).…”

Section: Discussionmentioning

confidence: 99%

“…The regulatory subset of CD4 ϩ T lymphocytes (CD4 ϩ CD25 ϩ ) can express FasL, but they do not directly induce monocyte/macrophage apoptosis through Fas (22). Rather, it is thought that they render macrophages susceptible to cell death by altering macrophage activation and programming (22,49). ␥␦ T lymphocytes comprise an additional T-lymphocyte subset that can induce apoptosis of activated macrophages in a FasL-dependent manner ex vivo (7,29).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, their role in the later phases of inflammation (including the regulation of AM⌽ apoptosis) has not been fully studied. Ex vivo studies have not demonstrated CD4 ϩ CD25 ϩ T-lymphocyte-mediated macrophage apoptosis (22). However, it is enticing to speculate that through the mechanisms described above, CD4…”

Section: Discussionmentioning

confidence: 99%

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Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation

Kearns

Barthel

Bednarek

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Janssen WJ. Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation. Am J Physiol Lung Cell Mol Physiol 307: L62-L70, 2014. First published May 16, 2014 doi:10.1152/ajplung.00273.2013.-Apoptosis of alveolar macrophages and their subsequent clearance by neighboring phagocytes are necessary steps in the resolution of acute pulmonary inflammation. We have recently identified that activation of the Fas death receptor on the cell surface of macrophages drives macrophage apoptosis. However, the source of the cognate ligand for Fas (FasL) responsible for induction of alveolar macrophage apoptosis is not defined. Given their known role in the resolution of inflammation and ability to induce macrophage apoptosis ex vivo, we hypothesized that T lymphocytes represented a critical source of FasL. To address this hypothesis, C57BL/6J and lymphocyte-deficient (Rag-1 Ϫ/Ϫ ) mice were exposed to intratracheal lipopolysaccharide to induce pulmonary inflammation. Furthermore, utilizing mice expressing nonfunctional FasL, we adoptively transferred donor lymphocytes into inflamed lymphocyte-deficient mice to characterize the effect of lymphocyte-derived FasL on alveolar macrophage apoptosis in the resolution of inflammation. Herein, evidence is presented that lymphocytes expressing FasL enhance alveolar macrophage apoptosis during the resolution of LPS-induced inflammation. Moreover, lymphocyte induction of alveolar macrophage apoptosis results in contraction of the alveolar macrophage pool, which occurs in a FasLdependent manner. Specifically, FasL-expressing CD8 ϩ T lymphocytes potently induce alveolar macrophage apoptosis and contraction of the alveolar macrophage pool. Together, these studies identify a novel role for CD8 ϩ T lymphocytes in the resolution of acute pulmonary inflammation. macrophage; resolution; alveolus; apoptosis; Fas ligand ACUTE INFLAMMATION IS CHARACTERIZED by recruitment of leukocytes, including neutrophils and mononuclear cells, to sites of injury or infection. For inflammation to resolve and the tissue to revert to its preinjured state, the recruited leukocytes must be cleared from the site. The processes that regulate the death and removal of neutrophils in the early resolution of inflammation are well described (14). However, the mechanisms that underlie the subsequent removal of macrophages in the resolution of inflammation have garnered less attention. We have recently identified that alveolar macrophages (AM⌽s) undergo apoptosis and local phagocytic clearance during the resolution of pulmonary inflammation and that this is required for the return of macrophage numbers to their preinflammatory levels (23).We have further demonstrated that AM⌽ apoptosis occurs via the extrinsic apoptotic pathway and proceeds through activation of the TNF-related death receptor Fas (CD95) on the macrophage cell surface (23). However, the cellular source of the cognate ligand for Fas (FasL) is unknown (12). The primary goal of the current study was to det...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation

Kearns

Barthel

Bednarek

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In peripheral T cells, a form of apoptosis induced by repeated T-cell receptor stimulation, known as activation-induced cell death (AICD), may be responsible for the peripheral deletion of autoreactive T cells [11]. AICD results from the interaction between Fas and Fas ligand, and activated T cells expressing both Fas and Fas ligand are killed either by autocrine or paracrine interactions [11,12]. Thus, AICD is an important mechanism of regulating overwhelming activation to prevent autoinflammation and autoimmunity.…”

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confidence: 99%

Activation‐dependent cell death of human monocytes is a novel mechanism of fine‐tuning inflammation and autoimmunity

et al. 2016

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In patients with juvenile idiopathic arthritis (JIA), increased release of IFN-γ and GM-CSF in cells infiltrating synovial tissue can be a potent driver of monocyte activation. Given the fundamental role of monocyte activation in remodeling the early phases of inflammatory responses, here we analyze the GM-CSF/IFN-γ induced activity of human monocytesin such a situation in vitro and in vivo. Monocytes from healthy donors were isolated and stimulated with GM-CSF ± IFN-γ. Monocyte activation and death were analyzed by flow cytometry, immunofluorescence microscopy, ELISA, and qPCR. T-cell GM-CSF/IFN-γ expression and monocyte function were determined in synovial fluid and peripheral blood from 15 patients with active JIA and 21 healthy controls. Simultaneous treatment with GM-CSF and IFN-γ induces cell death of monocytes. This cell death is partly cathepsin B-associated and has morphological characteristics of necrosis. Monocytes responding to costimulation with strong proinflammatory activities are consequently eliminated. Monocytes surviving this form of hyperactivation retain normal cytokine production. Cathepsin B activity is increased in monocytes isolated from synovial fluid from patients with active arthritis. Our data suggest GM-CSF/IFN-γ induced cell death of monocytes as a novel mechanism to eliminate overactivated monocytes, thereby potentially balancing inflammation and autoimmunity in JIA.Keywords: Arthritis · Autoimmunity · Caspase · Host defense ·Immune activation · Immune response Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Jan Däbritz e-mail: Jan.Daebritz@med.uni-rostock.de IntroductionThe pathogenesis of autoimmune joint diseases including juvenile idiopathic arthritis (JIA) involves a complex interplay of aberrantly activated innate and adaptive immune cells. In this context, C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu1998 Jan Däbritz et al. Eur. J. Immunol. 2016. 46: 1997 T cells are an important source of cytokines such as interferon gamma (IFN-γ). More recently, the importance of interleukin (IL)-23 and granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing T-helper (Th) 17 cells for autoimmunity has been established [1,2]. GM-CSF production by T cells has been linked to several autoimmune inflammatory diseases, including multiple sclerosis (MS), myocarditis, and arthritis [3]. The precise mechanism by which GM-CSF promotes autoimmunity has not been described, but the existing literature identifies GM-CSF as a key cytokine by which Th17 cells might activate myeloid cells, thereby linking the adaptive with the innate immune system in autoimmunity [4]. These data were generated in mouse models and their relation to the human system is not fully established, but notably an enrichment of IFN-γ/GM-CSF coproducing cells within the Th17 population in the inflamed joints of children with JIA has recently been demonstrated [5,6]. Both IFN-γ and GM-CSF are potent inducers of mono...

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Fas Signaling in Macrophages Promotes Chronicity in K/BxN Serum–Induced Arthritis

Huang

Birkett

Koessler

et al. 2013

Arthritis & Rheumatology

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Objective A non-apoptotic role for Fas signaling has been implicated in the regulation of inflammation and innate immunity. These studies were performed to elucidate the role of Fas signaling on macrophages in the development of arthritis. Methods K/BxN serum transfer arthritis was induced in a mouse line with Fas conditionally deleted in the myeloid lineage (Fasf/f, LyzMcre). The arthritis was assessed clinically and histologically. IL-1β, CXCL5, IL-10, IL-6 and gp96 expression was determined by ELISA. Bone marrow derived macrophages were activated by IL-1β and gp96. Cells were analyzed for phenotype and apoptosis by flow cytometry. Results The onset of arthritis in Fasf/f, LyzMcre mice was comparable to that observed in control mice, however, resolution was accelerated during the chronic phase. The attenuated arthritis was associated with reduced articular expression of the endogenous TLR2 ligand gp96 and the neutrophil chemokine CXCL5, and the enhanced expression of IL-10. Activation with IL-1β or gp96 induced increased IL-10 in Fas deficient, compared with control, macrophages. IL-10 suppressed IL-1β plus gp96 induced IL-6 and CXCL5. IL-1β-mediated activation of ERK, which regulates IL-10 expression, was increased in Fas-deficient macrophages. Conclusions Together, our observations suggest that impaired Fas signaling results in the enhanced expression of anti-inflammatory IL-10 and reduced gp96, which are associated with accelerated resolution of inflammation in the chronic phase of arthritis. These observations suggest that strategies to reduce endogenous TLR ligands and increase IL-10 may be beneficial in patients with RA.

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FAS/FAS-L dependent killing of activated human monocytes and macrophages by CD4+CD25− responder T cells, but not CD4+CD25+ regulatory T cells

Cited by 24 publications

References 54 publications

Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation

Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation

Activation‐dependent cell death of human monocytes is a novel mechanism of fine‐tuning inflammation and autoimmunity

Fas Signaling in Macrophages Promotes Chronicity in K/BxN Serum–Induced Arthritis

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