title: FAS/FAS-L dependent killing of activated human monocytes and macrophages by CD4+CD25- responder T cells, but not CD4+CD25+ regulatory T cells.
abstract: Conclusive resolution of an immune response is critical for the prevention of autoimmunity and chronic inflammation. We report that following co-culture with autologous CD4+CD25- responder T cells, human CD14+ monocytes and monocyte-derived macrophages become activated but also significantly more prone to apoptosis than monocytes/macrophages cultured alone. In contrast, in the presence of CD4+CD25+ regulatory T cells (Tregs), monocytes and macrophages survive whilst adopting an anti-inflammatory phenotype. The induction of monocyte death requires responder T cell activation and cell-contact between responder T cells and monocytes. We demonstrate a critical role for FAS/FAS-L ligation in responder T cell-induced monocyte killing since responder T cells, but not Tregs, upregulate FAS-ligand (FAS-L) mRNA, and induce FAS expression on monocytes. Furthermore, responder T cell-induced monocyte apoptosis is blocked by neutralising FAS/FAS-L interaction, and is not observed when monocytes from an autoimmune lymphoproliferative syndrome (ALPS) patient with complete FAS-deficiency are used as target cells. Finally, we show that responder T cell-induced killing of monocytes is impaired in patients with active rheumatoid arthritis (RA). Our data suggest that resolution of inflammation in the course of a healthy immune response is aided by the unperturbed killing of monocytes with inflammatory potential by responder T cells and the induction of longer-lived, Treg-induced, anti-inflammatory monocytes.
authors.affiliation: Centre for Molecular and Cellular Biology of Inflammation, Division of Immunology, Infection and Inflammatory Disease, King's College London, London SE1 1UL, UK.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Jagger
authors.forename: Hayley G
authors.initials: HG
authors.lastname: Evans
authors.forename: Gina J
authors.initials: GJ
authors.lastname: Walter
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Gullick
authors.forename: Bina
authors.initials: B
authors.lastname: Menon
authors.forename: Lucy E
authors.initials: LE
authors.lastname: Ballantine
authors.forename: Alastair
authors.initials: A
authors.lastname: Gracie
authors.forename: Aude
authors.initials: A
authors.lastname: Magerus-Chatinet
authors.forename: Machteld M
authors.initials: MM
authors.lastname: Tiemessen
authors.forename: Frederic
authors.initials: F
authors.lastname: Geissmann
authors.forename: Frederic
authors.initials: F
authors.lastname: Rieux-Laucat
authors.forename: Leonie S
authors.initials: LS
authors.lastname: Taams
mesh_terms: D017209:Apoptosis / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: C491901:FAS protein, human; D053222:Fas Ligand Protein; D053645:Interleukin-2 Receptor alpha Subunit; D018950:Lipopolysaccharide Receptors; D019014:fas Receptor