title: Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation.
abstract: Complement is viewed as a critical serum-operative component of innate immunity, with processing of its key component, C3, into activation fragments C3a and C3b confined to the extracellular space. We report here that C3 activation also occurred intracellularly. We found that the T cell-expressed protease cathepsin L (CTSL) processed C3 into biologically active C3a and C3b. Resting T cells contained stores of endosomal and lysosomal C3 and CTSL and substantial amounts of CTSL-generated C3a. While "tonic" intracellular C3a generation was required for homeostatic T cell survival, shuttling of this intracellular C3-activation-system to the cell surface upon T cell stimulation induced autocrine proinflammatory cytokine production. Furthermore, T cells from patients with autoimmune arthritis demonstrated hyperactive intracellular complement activation and interferon-γ production and CTSL inhibition corrected this deregulated phenotype. Importantly, intracellular C3a was observed in all examined cell populations, suggesting that intracellular complement activation might be of broad physiological significance.
authors: Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors: M Kathryn
authors: MK
authors: Liszewski
authors: MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors: Martin
authors: M
authors: Kolev
authors: MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors: Gaelle
authors: G
authors: Le Friec
authors: Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors: Marilyn
authors: M
authors: Leung
authors: Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors: Paula G
authors: PG
authors: Bertram
authors: MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors: Antonella F
authors: AF
authors: Fara
authors: Departamento de Immunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid 28006, Spain.
authors: Marta
authors: M
authors: Subias
authors: Centre for Complement and Inflammation Research, Imperial College, London SW7 2AZ, UK.
authors: Matthew C
authors: MC
authors: Pickering
authors: Université Joseph Fourier, GREPI/AGIM CNRS FRE3405, Grenoble, F-38041, France.
authors: Christian
authors: C
authors: Drouet
authors: Haartman Institute and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, FI-00014, Finland.
authors: Seppo
authors: S
authors: Meri
authors: Haartman Institute and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, FI-00014, Finland.
authors: T Petteri
authors: TP
authors: Arstila
authors: Haartman Institute and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, FI-00014, Finland.
authors: Pirkka T
authors: PT
authors: Pekkarinen
authors: Biomedical Research Centre, King's Health Partners, Guy's Hospital, London SE1 9RT, UK; Academic Department of Rheumatology, King's College London, London SE1 9RT, UK.
authors: Margaret
authors: M
authors: Ma
authors: Biomedical Research Centre, King's Health Partners, Guy's Hospital, London SE1 9RT, UK; Academic Department of Rheumatology, King's College London, London SE1 9RT, UK.
authors: Andrew
authors: A
authors: Cope
authors: Institute of Molecular Medicine and Cell Research, and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, D-79104, Germany.
authors: Thomas
authors: T
authors: Reinheckel
authors: Departamento de Immunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid 28006, Spain.
authors: Santiago
authors: S
authors: Rodriguez de Cordoba
authors: MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King's College London, Guy's Hospital, London SE1 9RT, UK; Biomedical Research Centre, King's Health Partners, Guy's Hospital, London SE1 9RT, UK.
authors: Behdad
authors: B
authors: Afzali
authors: Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors: John P
authors: JP
authors: Atkinson
authors: MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King's College London, Guy's Hospital, London SE1 9RT, UK. Electronic address: claudia.kemper@kcl.ac.uk.
authors: Claudia
authors: C
authors: Kemper
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000166:cytology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D056668:Cathepsin L / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D002648:Child; D003167:Complement Activation / Q000502:physiology*; D003176:Complement C3 / Q000276:immunology / Q000378:metabolism*; D015926:Complement C3a / Q000378:metabolism; D003179:Complement C3b / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D006706:Homeostasis / Q000502:physiology*; D006801:Humans
chemical_list: D003176:Complement C3; D015926:Complement C3a; D003179:Complement C3b; C534281:CTSL protein, human; D056668:Cathepsin L