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Immunity. 2013 Dec 12;39(6):1143-57. doi: 10.1016/j.immuni.2013.10.018. Epub 2013 Dec 5.

Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation.

Author information

1
Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
2
MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King's College London, Guy's Hospital, London SE1 9RT, UK.
3
Departamento de Immunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid 28006, Spain.
4
Centre for Complement and Inflammation Research, Imperial College, London SW7 2AZ, UK.
5
Université Joseph Fourier, GREPI/AGIM CNRS FRE3405, Grenoble, F-38041, France.
6
Haartman Institute and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, FI-00014, Finland.
7
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.
8
Institute of Molecular Medicine and Cell Research, and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, D-79104, Germany.
9
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.
10
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.

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.

PMID:
24315997
PMCID:
PMC3865363
DOI:
10.1016/j.immuni.2013.10.018
[Indexed for MEDLINE]
Free PMC Article
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