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Clinical MedicineIn-Press PreviewImmunology Open Access | 10.1172/JCI169496

KIR-HLA interactions extend human CD8+ T cell lifespan in vivo

Yan Zhang,1 Ada W.C. Yan,2 Lies Boelen,2 Linda Hadcocks,1 Arafa Salam,1 Daniel Padrosa Gispert,2 Loiza Spanos,1 Laura Mora Bitria,2 Neda Nemat-Gorgani,3 James A. Traherne,4 Chrissy H. Roberts,5 Danai A. Koftori,2 Graham P. Taylor,6 Daniel Forton,7 Paul J. Norman,8 Steven G.E. Marsh,9 Robert Busch,10 Derek Macallan,11 and Becca Asquith2

1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

Find articles by Zhang, Y. in: JCI | PubMed | Google Scholar

1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

Find articles by Yan, A. in: JCI | PubMed | Google Scholar |

1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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1Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom

2Department of Infectious Disease, Imperial College London, London, United Kingdom

3Department of Structural Biology and Department of Microbiology and Immunol, Stanford University School of Medicine, Stanford, United States of America

4Department of Pathology, University of Cambridge, Cambridge, United Kingdom

5Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

6Department of Infectious Disease, Imperial College of London, London, United Kingdom

7Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom

8Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States of America

9Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom

10School of Life and Health Sciences, University of Roehampton, London, United Kingdom

11Institute of Infection and Immunity, St George’s, University of London, London, United Kingdom

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Published April 18, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI169496.
Copyright © 2023, Zhang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 18, 2023 - Version history
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Abstract

BACKGROUND. There is increasing evidence, in transgenic mice and in vitro, that inhibitory killer cell immunoglobulin-like receptors (iKIRs) can modulate T cell responses. Furthermore, we have previously shown that iKIRs are an important determinant of T cell-mediated control of chronic virus infection and that these results are consistent with an increase in CD8+ T cell lifespan due to iKIR-ligand interactions. Here we test this prediction and investigate whether iKIRs affect T cell lifespan in humans in vivo.

METHODS. We used stable isotope labelling with deuterated water to quantify memory CD8+ T cell survival in healthy individuals and patients with chronic viral infections.

RESULTS. We showed that an individual’s iKIR-ligand genotype is a significant determinant of CD8+ T cell lifespan: in individuals with two iKIR-ligand gene pairs, memory CD8+ T cells survived on average for 125 days, in individuals with four iKIR-ligand gene pairs then memory CD8+ T cell lifespan was doubled to 250 days. Additionally, we showed that this survival advantage is independent of iKIR expression by the T cell of interest and further that iKIR-ligand genotype altered CD8+ and CD4+ T cell immune aging phenotype.

CONCLUSIONS. Together these data reveal an unexpectedly large impact of iKIR genotype on T cell survival.

FUNDING. Wellcome Trust, Medical Research Council, EU Horizon 2020, EU FP7, Leukemia and Lymphoma Research, National Institute of Health Research Imperial Biomedical Research Centre, Imperial College Research Fellowship, National Institute of Health, Jefferiss Trust.

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