Intracellular Complement Activation Sustains T Cell Homeostasis and Mediates Effector Differentiation

M. Kathryn Liszewski; Martin Kolev; Gaelle Le Friec; Marilyn Leung; Paula G. Bertram; Antonella F. Fara; Marta Subias; Matthew C. Pickering; Christian Drouet; Seppo Meri; T. Petteri Arstila; Pirkka T. Pekkarinen; Margaret Ma; Andrew Cope; Thomas Reinheckel; Santiago Rodriguez de Cordoba; Behdad Afzali; John P. Atkinson; Claudia Kemper

doi:10.1016/j.immuni.2013.10.018

Intracellular Complement Activation Sustains T Cell Homeostasis and Mediates Effector Differentiation

M. Kathryn Liszewski, Martin Kolev, Gaelle Le Friec, Marilyn Leung, Paula G. Bertram, Antonella F. Fara, Marta Subias, Matthew C. Pickering, Christian Drouet, Seppo Meri, T. Petteri Arstila, Pirkka T. Pekkarinen, Margaret Ma, Andrew Cope, Thomas Reinheckel, Santiago Rodriguez de Cordoba, Behdad Afzali, John P. Atkinson, Claudia Kemper^*

^*Corresponding author for this work

Institute of Systemic Inflamation Research

483 Citations (Scopus)

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 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.

Original language	English
Journal	Immunity
Volume	39
Issue number	6
Pages (from-to)	1143-1157
Number of pages	15
ISSN	1074-7613
DOIs	https://doi.org/10.1016/j.immuni.2013.10.018
Publication status	Published - 12.12.2013

Funding

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.

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Liszewski, M. K., Kolev, M., Le Friec, G., Leung, M., Bertram, P. G., Fara, A. F., Subias, M., Pickering, M. C., Drouet, C., Meri, S., Arstila, T. P., Pekkarinen, P. T., Ma, M., Cope, A., Reinheckel, T., Rodriguez de Cordoba, S., Afzali, B., Atkinson, J. P., & Kemper, C. (2013). Intracellular Complement Activation Sustains T Cell Homeostasis and Mediates Effector Differentiation. Immunity, 39(6), 1143-1157. https://doi.org/10.1016/j.immuni.2013.10.018

@article{b92867b53544486da011cfd5bbf6008b,

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 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.",

author = "Liszewski, \{M. Kathryn\} and Martin Kolev and \{Le Friec\}, Gaelle and Marilyn Leung and Bertram, \{Paula G.\} and Fara, \{Antonella F.\} and Marta Subias and Pickering, \{Matthew C.\} and Christian Drouet and Seppo Meri and Arstila, \{T. Petteri\} and Pekkarinen, \{Pirkka T.\} and Margaret Ma and Andrew Cope and Thomas Reinheckel and \{Rodriguez de Cordoba\}, Santiago and Behdad Afzali and Atkinson, \{John P.\} and Claudia Kemper",

note = "Funding Information: We thank Marina Botto (Imperial College London, UK) and Adrian Hayday (King{\textquoteright}s College London, UK) for critical discussions on manuscript composition. We thank J{\"o}rg K{\"o}hl (University of L{\"u}beck, 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 Jus{\'e}lius 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{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust and King{\textquoteright}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. ",

year = "2013",

month = dec,

day = "12",

doi = "10.1016/j.immuni.2013.10.018",

language = "English",

volume = "39",

pages = "1143--1157",

journal = "Immunity",

issn = "1074-7613",

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Liszewski, MK, Kolev, M, Le Friec, G, Leung, M, Bertram, PG, Fara, AF, Subias, M, Pickering, MC, Drouet, C, Meri, S, Arstila, TP, Pekkarinen, PT, Ma, M, Cope, A, Reinheckel, T, Rodriguez de Cordoba, S, Afzali, B, Atkinson, JP & Kemper, C 2013, 'Intracellular Complement Activation Sustains T Cell Homeostasis and Mediates Effector Differentiation', Immunity, vol. 39, no. 6, pp. 1143-1157. https://doi.org/10.1016/j.immuni.2013.10.018

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 - https://www.scopus.com/pages/publications/84890226478

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 -

Intracellular Complement Activation Sustains T Cell Homeostasis and Mediates Effector Differentiation

Abstract

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Research Areas and Centers

UN SDGs

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