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Nat Commun. 2018 Oct 10;9(1):4186. doi: 10.1038/s41467-018-06706-z.

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

Author information

1
Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy.
2
School of Immunology and Microbial Sciences, King's College London, London, UK.
3
Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA.
4
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
5
Service de Néphrologie adulte, Hôpital Necker, Paris, France.
6
Nephrologie,Transplantation, Dialyse, CHU Bordeaux, and CNRS-UMR 5164 Immuno ConcEpT, Université de Bordeaux, Bordeaux, France.
7
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, and INSERM UMR S1138, Centre de Recherche des Cordeliers, Paris, France.
8
Department of Renal Medicine, Nottingham University Hospitals, NHS Trust, Nottingham, UK.
9
National Renal Complement Therapeutics Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
10
Immunoregulation Section, Kidney Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA.
11
UK National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Campus, London, UK. H.lachmann@ucl.ac.uk.
12
School of Immunology and Microbial Sciences, King's College London, London, UK. Claudia.kemper@nih.gov.
13
Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA. Claudia.kemper@nih.gov.
14
Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany. Claudia.kemper@nih.gov.

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.

PMID:
30305631
PMCID:
PMC6180132
DOI:
10.1038/s41467-018-06706-z
[Indexed for MEDLINE]
Free PMC Article

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