Sestrins induce natural killer function in senescent-like CD8+ T cells

Branca I Pereira; Roel P H De Maeyer; Luciana P Covre; Djamel Nehar-Belaid; Alessio Lanna; Sophie Ward; Radu Marches; Emma S Chambers; Daniel C O Gomes; Natalie E Riddell; Mala K Maini; Vitor H Teixeira; Samuel M Janes; Derek W Gilroy; Anis Larbi; Neil A Mabbott; Duygu Ucar; George A Kuchel; Sian M Henson; Jessica Strid; Jun H Lee; Jacques Banchereau; Arne N Akbar

doi:10.1038/s41590-020-0643-3

Sestrins induce natural killer function in senescent-like CD8⁺ T cells

Nat Immunol. 2020 Jun;21(6):684-694. doi: 10.1038/s41590-020-0643-3. Epub 2020 Mar 30.

Authors

Branca I Pereira^#¹, Roel P H De Maeyer^#¹, Luciana P Covre^#^{1

2}, Djamel Nehar-Belaid^#³, Alessio Lanna^{1

4}, Sophie Ward⁵, Radu Marches³, Emma S Chambers¹, Daniel C O Gomes², Natalie E Riddell^{1

6}, Mala K Maini¹, Vitor H Teixeira⁷, Samuel M Janes⁷, Derek W Gilroy⁸, Anis Larbi⁹, Neil A Mabbott¹⁰, Duygu Ucar³, George A Kuchel¹¹, Sian M Henson¹², Jessica Strid⁵, Jun H Lee¹³, Jacques Banchereau³, Arne N Akbar¹⁴

Affiliations

¹ Division of Infection and Immunity, University College London, London, UK.
² Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, Brazil.
³ The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
⁴ Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁵ Department of Medicine, Imperial College London, London, UK.
⁶ Faculty of Health & Medical Sciences, University of Surrey, Guildford, UK.
⁷ Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK.
⁸ Division of Medicine, University College London, London, UK.
⁹ Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.
¹⁰ Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK.
¹¹ University of Connecticut Center on Aging, University of Connecticut, Farmington, CT, USA.
¹² William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
¹³ Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
¹⁴ Division of Infection and Immunity, University College London, London, UK. a.akbar@ucl.ac.uk.

^# Contributed equally.

Abstract

Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8⁺ T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27^-CD28^-CD8⁺ T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D-DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27^-CD28^-CD8⁺ T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27^-CD28^-CD8⁺ T cells to acquire a broad-spectrum, innate-like killing activity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / metabolism*
Cellular Senescence / immunology*
Cytotoxicity, Immunologic
Gene Expression Profiling
Humans
Killer Cells, Natural / immunology*
Killer Cells, Natural / metabolism*
Membrane Proteins / metabolism
NK Cell Lectin-Like Receptor Subfamily K / metabolism
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Receptors, Antigen, T-Cell / metabolism
Receptors, Natural Killer Cell / metabolism
Signal Transduction
Yellow Fever / genetics
Yellow Fever / immunology
Yellow Fever / metabolism
Yellow Fever / virology
Yellow fever virus / immunology

Substances

Adaptor Proteins, Signal Transducing
Membrane Proteins
NK Cell Lectin-Like Receptor Subfamily K
Nuclear Proteins
Receptors, Antigen, T-Cell
Receptors, Natural Killer Cell
SESN2 protein, human
TYROBP protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding