Complement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism

Giuseppina Arbore; Erin E. West; Jubayer Rahman; Gaelle Le Friec; Nathalie Niyonzima; Mehdi Pirooznia; Ilker Tunc; Polychronis Pavlidis; Nicholas Powell; Yuesheng Li; Poching Liu; Aude Servais; Lionel Couzi; Veronique Fremeaux-Bacchi; Leo Placais; Alastair Ferraro; Patrick R. Walsh; David Kavanagh; Behdad Afzali; Paul Lavender; Helen J. Lachmann; Claudia Kemper

doi:10.1038/s41467-018-06706-z

Complement receptor CD46 co-stimulates optimal human CD8⁺ T cell effector function via fatty acid metabolism

Giuseppina Arbore, Erin E. West, Jubayer Rahman, Gaelle Le Friec, Nathalie Niyonzima, Mehdi Pirooznia, Ilker Tunc, Polychronis Pavlidis, Nicholas Powell, Yuesheng Li, Poching Liu, Aude Servais, Lionel Couzi, Veronique Fremeaux-Bacchi, Leo Placais, Alastair Ferraro, Patrick R. Walsh, David Kavanagh, Behdad Afzali, Paul LavenderHelen J. Lachmann, Claudia Kemper^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Systemische Entzündungsforschung

99 Zitate (Scopus)

Abstract

The induction of human CD4⁺ Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4⁺ T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8⁺ T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis. Surprisingly, although CTLs express NLRP3, a canonical NLRP3 inflammasome is not required for normal human CTL activity, as CTLs from patients with hyperactive NLRP3 activity function normally. These findings establish autocrine complement and CD46 activity as integral components of normal human CTL biology, and, since CD46 is only present in humans, emphasize the divergent roles of innate immune sensors between mice and men.

Originalsprache	Englisch
Aufsatznummer	4186
Zeitschrift	Nature Communications
Jahrgang	9
Ausgabenummer	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-018-06706-z
Publikationsstatus	Veröffentlicht - 01.12.2018

Fördermittel

1Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy. 2School of Immunology and Microbial Sciences, King’s College London, London, UK. 3Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA. 4Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. 5Service de Néphrologie adulte, Hôpital Necker, Paris, France. 6Nephrologie,Transplantation, Dialyse, CHU Bordeaux, and CNRS-UMR 5164 Immuno ConcEpT, Université de Bordeaux, Bordeaux, France. 7Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, and INSERM UMR S1138, Centre de Recherche des Cordeliers, Paris, France. 8Department of Renal Medicine, Nottingham University Hospitals, NHS Trust, Nottingham, UK. 9National Renal Complement Therapeutics Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. 10Immunoregulation Section, Kidney Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA. 11UK National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Campus, London, UK. 12Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany. These authors contributed equally: Giuseppina Arbore, Erin E. West, Jubayer Rahman Correspondence and requests for materials should be addressed to H.J.L. (email: [email protected]) or to C.K. (email: [email protected]) We thank the patients and the healthy donors for their support. We also thank the Bioinformatics and Computational Biology Core as well as the DNA Sequencing and Genomics Core at NHLBI for sample processing and help with the analyses. This work was financed by the MRC Centre grant MR/J006742/1, an EU-funded Innovative Medicines Initiative BTCURE (C.K.), a Wellcome Trust Investigator Award (C.K), a Wellcome Trust Clinical Fellowship (B.A.), the King’s Bioscience Institute at King’s College London (G.A.), a grant from the Guy’s and St. Thomas’ Charity (C.K., B.A., and N.P.), The King’s College London BRC Genomics Facility, the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London, [in part] by the Intramural Research Program of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH.

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

Dokumente

10.1038/s41467-018-06706-z

Weitere Links

Link to publication in Scopus

Zitieren

Arbore, G., West, E. E., Rahman, J., Le Friec, G., Niyonzima, N., Pirooznia, M., Tunc, I., Pavlidis, P., Powell, N., Li, Y., Liu, P., Servais, A., Couzi, L., Fremeaux-Bacchi, V., Placais, L., Ferraro, A., Walsh, P. R., Kavanagh, D., Afzali, B., ... Kemper, C. (2018). Complement receptor CD46 co-stimulates optimal human CD8⁺ T cell effector function via fatty acid metabolism. Nature Communications, 9(1), Artikel 4186. https://doi.org/10.1038/s41467-018-06706-z

@article{ca1c6efacf1b48628f7211199944f775,

title = "Complement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism",

abstract = "The induction of human CD4+ Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4+ T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8+ T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis. Surprisingly, although CTLs express NLRP3, a canonical NLRP3 inflammasome is not required for normal human CTL activity, as CTLs from patients with hyperactive NLRP3 activity function normally. These findings establish autocrine complement and CD46 activity as integral components of normal human CTL biology, and, since CD46 is only present in humans, emphasize the divergent roles of innate immune sensors between mice and men.",

author = "Giuseppina Arbore and West, \{Erin E.\} and Jubayer Rahman and \{Le Friec\}, Gaelle and Nathalie Niyonzima and Mehdi Pirooznia and Ilker Tunc and Polychronis Pavlidis and Nicholas Powell and Yuesheng Li and Poching Liu and Aude Servais and Lionel Couzi and Veronique Fremeaux-Bacchi and Leo Placais and Alastair Ferraro and Walsh, \{Patrick R.\} and David Kavanagh and Behdad Afzali and Paul Lavender and Lachmann, \{Helen J.\} and Claudia Kemper",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-06706-z",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "1751-8628",

publisher = "John Wiley \& Sons Inc.",

number = "1",

}

Arbore, G, West, EE, Rahman, J, Le Friec, G, Niyonzima, N, Pirooznia, M, Tunc, I, Pavlidis, P, Powell, N, Li, Y, Liu, P, Servais, A, Couzi, L, Fremeaux-Bacchi, V, Placais, L, Ferraro, A, Walsh, PR, Kavanagh, D, Afzali, B, Lavender, P, Lachmann, HJ & Kemper, C 2018, 'Complement receptor CD46 co-stimulates optimal human CD8⁺ T cell effector function via fatty acid metabolism', Nature Communications, Jg. 9, Nr. 1, 4186. https://doi.org/10.1038/s41467-018-06706-z

TY - JOUR

T1 - Complement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism

AU - Arbore, Giuseppina

AU - West, Erin E.

AU - Rahman, Jubayer

AU - Le Friec, Gaelle

AU - Niyonzima, Nathalie

AU - Pirooznia, Mehdi

AU - Tunc, Ilker

AU - Pavlidis, Polychronis

AU - Powell, Nicholas

AU - Li, Yuesheng

AU - Liu, Poching

AU - Servais, Aude

AU - Couzi, Lionel

AU - Fremeaux-Bacchi, Veronique

AU - Placais, Leo

AU - Ferraro, Alastair

AU - Walsh, Patrick R.

AU - Kavanagh, David

AU - Afzali, Behdad

AU - Lavender, Paul

AU - Lachmann, Helen J.

AU - Kemper, Claudia

PY - 2018/12/1

Y1 - 2018/12/1

N2 - The induction of human CD4+ Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4+ T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8+ T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis. Surprisingly, although CTLs express NLRP3, a canonical NLRP3 inflammasome is not required for normal human CTL activity, as CTLs from patients with hyperactive NLRP3 activity function normally. These findings establish autocrine complement and CD46 activity as integral components of normal human CTL biology, and, since CD46 is only present in humans, emphasize the divergent roles of innate immune sensors between mice and men.

AB - The induction of human CD4+ Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4+ T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8+ T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis. Surprisingly, although CTLs express NLRP3, a canonical NLRP3 inflammasome is not required for normal human CTL activity, as CTLs from patients with hyperactive NLRP3 activity function normally. These findings establish autocrine complement and CD46 activity as integral components of normal human CTL biology, and, since CD46 is only present in humans, emphasize the divergent roles of innate immune sensors between mice and men.

UR - https://www.scopus.com/pages/publications/85054762660

U2 - 10.1038/s41467-018-06706-z

DO - 10.1038/s41467-018-06706-z

M3 - Journal articles

C2 - 30305631

AN - SCOPUS:85054762660

SN - 1751-8628

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4186

ER -