TY - JOUR
T1 - Intracellular Complement Activation Sustains T Cell Homeostasis and Mediates Effector Differentiation
AU - Liszewski, M. Kathryn
AU - Kolev, Martin
AU - Le Friec, Gaelle
AU - Leung, Marilyn
AU - Bertram, Paula G.
AU - Fara, Antonella F.
AU - Subias, Marta
AU - Pickering, Matthew C.
AU - Drouet, Christian
AU - Meri, Seppo
AU - Arstila, T. Petteri
AU - Pekkarinen, Pirkka T.
AU - Ma, Margaret
AU - Cope, Andrew
AU - Reinheckel, Thomas
AU - Rodriguez de Cordoba, Santiago
AU - Afzali, Behdad
AU - Atkinson, John P.
AU - Kemper, Claudia
N1 - Funding Information:
We thank Marina Botto (Imperial College London, UK) and Adrian Hayday (King’s College London, UK) for critical discussions on manuscript composition. We thank Jörg Köhl (University of Lübeck, Germany) for the anti-C3a neo-epitope antibody and Margaret So (University of Arizona, USA) for the anti-CD46 CYT-1 antibody. This work was supported by an MRC Research Grant G1002165 (C.K.), an EU-funded Innovative Medicines Initiative BTCURE (A.C., M.M., and C.K.), a Wellcome Trust Intermediate Research Fellowship (B.A.), and the Sigrid Jusélius Foundation, Helsinki, Finland, and the Spanish MICINN and CM projects SAF2011-265835 and S2010/BMD-2316' (S.R.d.C.). The research was also funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The authors acknowledge the support of the MRC Centre for Transplantation. Support was also provided by the National Institutes of Health (R01 grant GM0099111 to J.P.A.) and the Antibody Production Facility of the Rheumatic Diseases Core Center at Washington University in Saint Louis. Research reported in this publication is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health, under Award Number P30AR048335.
PY - 2013/12/12
Y1 - 2013/12/12
N2 - 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 Tcell-expressed protease cathepsin L (CTSL) processed C3 into biologically active C3a and C3b. Resting Tcells 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 Tcell survival, shuttling of this intracellular C3-activation-system to the cell surface upon Tcell stimulation induced autocrine proinflammatory cytokine production. Furthermore, Tcells 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.
AB - 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 Tcell-expressed protease cathepsin L (CTSL) processed C3 into biologically active C3a and C3b. Resting Tcells 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 Tcell survival, shuttling of this intracellular C3-activation-system to the cell surface upon Tcell stimulation induced autocrine proinflammatory cytokine production. Furthermore, Tcells 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.
UR - http://www.scopus.com/inward/record.url?scp=84890226478&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2013.10.018
DO - 10.1016/j.immuni.2013.10.018
M3 - Journal articles
AN - SCOPUS:84890226478
SN - 1074-7613
VL - 39
SP - 1143
EP - 1157
JO - Immunity
JF - Immunity
IS - 6
ER -
