Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition
Abstract
Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here we show that senescent dermal fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8+ T cells to inhibit immune responses against senescent cells. HLA-E expression is induced by senescence-associated secretary phenotype-related pro-inflammatory cytokines, and is regulated by p38 MAP kinase signalling in vitro. Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing.
- Authors:
-
[1];
[1];
- Univ. College London (UCL) (United Kingdom)
- Buck Inst. for Research on Aging, Novato, CA (United States)
- Newcastle Univ., Newcastle upon Tyne (United Kingdom)
- Northumbria Univ., Newcastle upon Tyne (United Kingdom)
- Buck Inst. for Research on Aging, Novato, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1546687
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES
Citation Formats
Pereira, Branca I., Devine, Oliver P., Vukmanovic-Stejic, Milica, Chambers, Emma S., Subramanian, Priya, Patel, Neil, Virasami, Alex, Sebire, Neil J., Kinsler, Veronica, Valdovinos, Alexis, LeSaux, Claude Jourdan, Passos, João F., Antoniou, Antony, Rustin, Malcom H. A., Campisi, Judith, and Akbar, Arne N. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. United States: N. p., 2019.
Web. doi:10.1038/s41467-019-10335-5.
Pereira, Branca I., Devine, Oliver P., Vukmanovic-Stejic, Milica, Chambers, Emma S., Subramanian, Priya, Patel, Neil, Virasami, Alex, Sebire, Neil J., Kinsler, Veronica, Valdovinos, Alexis, LeSaux, Claude Jourdan, Passos, João F., Antoniou, Antony, Rustin, Malcom H. A., Campisi, Judith, & Akbar, Arne N. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. United States. https://doi.org/10.1038/s41467-019-10335-5
Pereira, Branca I., Devine, Oliver P., Vukmanovic-Stejic, Milica, Chambers, Emma S., Subramanian, Priya, Patel, Neil, Virasami, Alex, Sebire, Neil J., Kinsler, Veronica, Valdovinos, Alexis, LeSaux, Claude Jourdan, Passos, João F., Antoniou, Antony, Rustin, Malcom H. A., Campisi, Judith, and Akbar, Arne N. Mon .
"Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition". United States. https://doi.org/10.1038/s41467-019-10335-5. https://www.osti.gov/servlets/purl/1546687.
@article{osti_1546687,
title = {Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition},
author = {Pereira, Branca I. and Devine, Oliver P. and Vukmanovic-Stejic, Milica and Chambers, Emma S. and Subramanian, Priya and Patel, Neil and Virasami, Alex and Sebire, Neil J. and Kinsler, Veronica and Valdovinos, Alexis and LeSaux, Claude Jourdan and Passos, João F. and Antoniou, Antony and Rustin, Malcom H. A. and Campisi, Judith and Akbar, Arne N.},
abstractNote = {Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here we show that senescent dermal fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8+ T cells to inhibit immune responses against senescent cells. HLA-E expression is induced by senescence-associated secretary phenotype-related pro-inflammatory cytokines, and is regulated by p38 MAP kinase signalling in vitro. Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing.},
doi = {10.1038/s41467-019-10335-5},
journal = {Nature Communications},
number = 1,
volume = 10,
place = {United States},
year = {2019},
month = {6}
}
Free Publicly Available Full Text
Publisher's Version of Record
Other availability
Search WorldCat to find libraries that may hold this journal
Cited by: 27 works
Citation information provided by
Web of Science
Web of Science
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.
Works referenced in this record:
The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor
journal, July 2005
- Gasser, Stephan; Orsulic, Sandra; Brown, Eric J.
- Nature, Vol. 436, Issue 7054
PKC signaling prevents irradiation-induced apoptosis of primary human fibroblasts
journal, February 2013
- Bluwstein, A.; Kumar, N.; Léger, K.
- Cell Death & Disease, Vol. 4, Issue 2
The Clinical Potential of Senolytic Drugs
journal, September 2017
- Kirkland, James L.; Tchkonia, Tamara; Zhu, Yi
- Journal of the American Geriatrics Society, Vol. 65, Issue 10
Identification and characterization of a fibroblast marker: FSP1
journal, July 1995
- Strutz, F.
- The Journal of Cell Biology, Vol. 130, Issue 2
Cellular senescence mediates fibrotic pulmonary disease
journal, February 2017
- Schafer, Marissa J.; White, Thomas A.; Iijima, Koji
- Nature Communications, Vol. 8, Issue 1
Human NK cells display major phenotypic and functional changes over the life span: Human NK cell features over the life span
journal, April 2010
- Le Garff-Tavernier, Magali; Béziat, Vivien; Decocq, Julie
- Aging Cell, Vol. 9, Issue 4
p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells
journal, September 2013
- Iannello, Alexandre; Thompson, Thornton W.; Ardolino, Michele
- The Journal of Experimental Medicine, Vol. 210, Issue 10
The other Janus face of Qa-1 and HLA-E: diverse peptide repertoires in times of stress
journal, November 2010
- van Hall, Thorbald; Oliveira, Claudia C.; Joosten, Simone A.
- Microbes and Infection, Vol. 12, Issue 12-13
Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer
journal, April 2012
- Rudin, C. M.; Hann, C. L.; Garon, E. B.
- Clinical Cancer Research, Vol. 18, Issue 11
The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression
journal, January 2010
- Coppé, Jean-Philippe; Desprez, Pierre-Yves; Krtolica, Ana
- Annual Review of Pathology: Mechanisms of Disease, Vol. 5, Issue 1
Human NKG2A overrides NKG2C effector functions to prevent autoreactivity of NK cells
journal, April 2011
- Béziat, Vivien; Hervier, Baptiste; Achour, Abla
- Blood, Vol. 117, Issue 16
The inhibitory NK cell receptor CD94/NKG2A and the activating receptor CD94/NKG2C bind the top of HLA-E through mostly shared but partly distinct sets of HLA-E residues
journal, January 2004
- Wada, Haruka; Matsumoto, Naoki; Maenaka, Katsumi
- European Journal of Immunology, Vol. 34, Issue 1
The impact of ageing on natural killer cell function and potential consequences for health in older adults
journal, September 2013
- Hazeldine, Jon; Lord, Janet M.
- Ageing Research Reviews, Vol. 12, Issue 4
KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells
journal, June 2009
- Henson, Sian M.; Franzese, Ornella; Macaulay, Richard
- Blood, Vol. 113, Issue 26
BRAFE600-associated senescence-like cell cycle arrest of human naevi
journal, August 2005
- Michaloglou, Chrysiis; Vredeveld, Liesbeth C. W.; Soengas, Maria S.
- Nature, Vol. 436, Issue 7051
Chronic Inflammation (Inflammaging) and Its Potential Contribution to Age-Associated Diseases
journal, May 2014
- Franceschi, C.; Campisi, J.
- The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, Vol. 69, Issue Suppl 1
CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence
journal, March 2008
- Petrie, Emma J.; Clements, Craig S.; Lin, Jie
- The Journal of Experimental Medicine, Vol. 205, Issue 3
Characterization of monoclonal antibodies recognizing HLA-G or HLA-E: new tools to analyze the expression of nonclassical HLA class I molecules
journal, March 2003
- Menier, Catherine; Saez, Berta; Horejsi, Vaclav
- Human Immunology, Vol. 64, Issue 3
p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype: p38 regulates the senescence secretory phenotype
journal, March 2011
- Freund, Adam; Patil, Christopher K.; Campisi, Judith
- The EMBO Journal, Vol. 30, Issue 8
Senescence of T Lymphocytes: Implications for Enhancing Human Immunity
journal, December 2016
- Akbar, Arne N.; Henson, Sian M.; Lanna, Alessio
- Trends in Immunology, Vol. 37, Issue 12
Interactions between HLA-G and HLA-E in Physiological and Pathological Conditions
journal, August 2014
- Morandi, Fabio; Pistoia, Vito
- Frontiers in Immunology, Vol. 5
An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA
journal, December 2014
- Demaria, Marco; Ohtani, Naoko; Youssef, Sameh A.
- Developmental Cell, Vol. 31, Issue 6
Senescence and aging: Causes, consequences, and therapeutic avenues
journal, November 2017
- McHugh, Domhnall; Gil, Jesús
- The Journal of Cell Biology, Vol. 217, Issue 1
Nk cell Recognition
journal, April 2005
- Lanier, Lewis L.
- Annual Review of Immunology, Vol. 23, Issue 1
Aging, Cellular Senescence, and Cancer
journal, February 2013
- Campisi, Judith
- Annual Review of Physiology, Vol. 75, Issue 1
Enhancing Chemotherapy Efficacy in Pten -Deficient Prostate Tumors by Activating the Senescence-Associated Antitumor Immunity
journal, October 2014
- Toso, Alberto; Revandkar, Ajinkya; Di Mitri, Diletta
- Cell Reports, Vol. 9, Issue 1
Immune surveillance of senescent cells--biological significance in cancer- and non-cancer pathologies
journal, April 2012
- Hoenicke, L.; Zender, L.
- Carcinogenesis, Vol. 33, Issue 6
The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration
journal, January 2017
- Ritschka, Birgit; Storer, Mekayla; Mas, Alba
- Genes & Development, Vol. 31, Issue 2
Skin Punch Biopsy Explant Culture for Derivation of Primary Human Fibroblasts
journal, January 2013
- Vangipuram, Malini; Ting, Dennis; Kim, Sam
- Journal of Visualized Experiments, Issue 77
Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E
journal, January 2016
- Hansen, S. G.; Wu, H. L.; Burwitz, B. J.
- Science, Vol. 351, Issue 6274
Reciprocal age related change in natural killer cell receptors for MHC class I
journal, June 2005
- Lutz, Charles T.; Moore, Mikel B.; Bradley, Sarah
- Mechanisms of Ageing and Development, Vol. 126, Issue 6-7
Role of non-classical MHC class I molecules in cancer immunosuppression
journal, November 2013
- Kochan, Grazyna; Escors, David; Breckpot, Karine
- OncoImmunology, Vol. 2, Issue 11
The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells
journal, August 2014
- Lanna, Alessio; Henson, Sian M.; Escors, David
- Nature Immunology, Vol. 15, Issue 10
A Signal Peptide Derived from hsp60 Binds HLA-E and Interferes with CD94/NKG2A Recognition
journal, December 2002
- Michaëlsson, Jakob; Teixeira de Matos, Cristina; Achour, Adnane
- The Journal of Experimental Medicine, Vol. 196, Issue 11
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
journal, January 2007
- Xue, Wen; Zender, Lars; Miething, Cornelius
- Nature, Vol. 445, Issue 7128
A genomics approach identifies senescence-specific gene expression regulation
journal, May 2014
- Lackner, Daniel H.; Hayashi, Makoto T.; Cesare, Anthony J.
- Aging Cell, Vol. 13, Issue 5
Senescence of Activated Stellate Cells Limits Liver Fibrosis
journal, August 2008
- Krizhanovsky, Valery; Yon, Monica; Dickins, Ross A.
- Cell, Vol. 134, Issue 4
Senescence surveillance of pre-malignant hepatocytes limits liver cancer development
journal, November 2011
- Kang, Tae-Won; Yevsa, Tetyana; Woller, Norman
- Nature, Vol. 479, Issue 7374
Oncogene-Expressing Senescent Melanocytes Up-Regulate MHC Class II, a Candidate Melanoma Suppressor Function
journal, October 2017
- van Tuyn, John; Jaber-Hijazi, Farah; MacKenzie, Douglas
- Journal of Investigative Dermatology, Vol. 137, Issue 10
The number of p16INK4a positive cells in human skin reflects biological age: p16INK4a in human skin reflects biological age
journal, June 2012
- Waaijer, Mariëtte E. C.; Parish, William E.; Strongitharm, Barbara H.
- Aging Cell, Vol. 11, Issue 4
Naturally occurring p16Ink4a-positive cells shorten healthy lifespan
journal, February 2016
- Baker, Darren J.; Childs, Bennett G.; Durik, Matej
- Nature, Vol. 530, Issue 7589
Regulation of Ligands for the NKG2D Activating Receptor
journal, March 2013
- Raulet, David H.; Gasser, Stephan; Gowen, Benjamin G.
- Annual Review of Immunology, Vol. 31, Issue 1
The role of senescent cells in ageing
journal, May 2014
- van Deursen, Jan M.
- Nature, Vol. 509, Issue 7501
Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion
journal, July 2009
- Rodier, Francis; Coppé, Jean-Philippe; Patil, Christopher K.
- Nature Cell Biology, Vol. 11, Issue 8
Forging a signature of in vivo senescence
journal, June 2015
- Sharpless, Norman E.; Sherr, Charles J.
- Nature Reviews Cancer, Vol. 15, Issue 7
Evaluating the Role of p38 MAPK in the Accelerated Cell Senescence of Werner Syndrome Fibroblasts
journal, April 2016
- Davis, Terence; Brook, Amy; Rokicki, Michal
- Pharmaceuticals, Vol. 9, Issue 2
Effects of anti-NKG2A antibody administration on leukemia and normal hematopoietic cells
journal, December 2015
- Ruggeri, L.; Urbani, E.; Andre, P.
- Haematologica, Vol. 101, Issue 5
Relationship between CD107a expression and cytotoxic activity
journal, January 2009
- Aktas, Esin; Kucuksezer, Umut Can; Bilgic, Sema
- Cellular Immunology, Vol. 254, Issue 2
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
journal, November 2011
- Baker, Darren J.; Wijshake, Tobias; Tchkonia, Tamar
- Nature, Vol. 479, Issue 7372
NKG2D ligands mediate immunosurveillance of senescent cells
journal, February 2016
- Sagiv, Adi; Burton, Dominick G. A.; Moshayev, Zhana
- Aging, Vol. 8, Issue 2
A complex secretory program orchestrated by the inflammasome controls paracrine senescence
journal, June 2013
- Acosta, Juan Carlos; Banito, Ana; Wuestefeld, Torsten
- Nature Cell Biology, Vol. 15, Issue 8
Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression
journal, October 2016
- Eggert, Tobias; Wolter, Katharina; Ji, Juling
- Cancer Cell, Vol. 30, Issue 4
ATM-ATR–dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype
journal, April 2009
- Soriani, Alessandra; Zingoni, Alessandra; Cerboni, Cristina
- Blood, Vol. 113, Issue 15
Effect of age and CMV on NK cell subpopulations
journal, June 2014
- Campos, Carmen; Pera, Alejandra; Sanchez-Correa, Beatriz
- Experimental Gerontology, Vol. 54
Cellular senescence: Immunosurveillance and future immunotherapy
journal, May 2018
- Burton, Dominick G. A.; Stolzing, Alexandra
- Ageing Research Reviews, Vol. 43
Expression and release of soluble HLA-E is an immunoregulatory feature of endothelial cell activation
journal, December 2006
- Coupel, Stéphanie; Moreau, Anne; Hamidou, Mohamed
- Blood, Vol. 109, Issue 7
PKC signaling prevents irradiation-induced apoptosis of primary human fibroblasts
text, January 2013
- Bluwstein, Andrej; Kumar, Nitin; Léger, Karolin
- ETH Zurich
Senescence of Activated Stellate Cells Limits Liver Fibrosis
journal, October 2008
- Krizhanovsky, Valery; Yon, Monica; Dickins, Ross A.
- Cell, Vol. 135, Issue 1
Works referencing / citing this record:
Risk profiling using metabolomic characteristics for susceptible individuals of drug-induced liver injury caused by Polygonum multiflorum
journal, October 2019
- Zhang, Le; Niu, Ming; Wei, Ai-wu
- Archives of Toxicology, Vol. 94, Issue 1
Senescence and the Impact on Biodistribution of Different Nanosystems: the Discrepancy on Tissue Deposition of Graphene Quantum Dots, Polycaprolactone Nanoparticle and Magnetic Mesoporous Silica Nanoparticles in Young and Elder Animals
journal, January 2020
- dos Reis, Sara Rhaissa Rezende; Pinto, Suyene Rocha; de Menezes, Frederico Duarte
- Pharmaceutical Research, Vol. 37, Issue 3
Skin barrier immunity and ageing
journal, December 2019
- Chambers, Emma S.; Vukmanovic‐Stejic, Milica
- Immunology, Vol. 160, Issue 2
Compartmentalized cytotoxic immune response leads to distinct pathogenic roles of natural killer and senescent CD8 + T cells in human cutaneous leishmaniasis
journal, January 2020
- Covre, Luciana Polaco; Devine, Oliver Patrick; Garcia de Moura, Renan
- Immunology, Vol. 159, Issue 4
Virtual Screening of Potential Anti-fatigue Mechanism of Polygonati Rhizoma Based on Network Pharmacology
journal, January 2020
- Wang, Ze-Feng; Hu, Ye-Qing; Wu, Qi-Guo
- Combinatorial Chemistry & High Throughput Screening, Vol. 22, Issue 9
Environmental Exposures and Asthma Development: Autophagy, Mitophagy, and Cellular Senescence
journal, November 2019
- Sachdeva, Karan; Do, Danh C.; Zhang, Yan
- Frontiers in Immunology, Vol. 10