skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: 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];  [1]; ORCiD logo [1];  [1];  [1]; ORCiD logo [1];  [1];  [1];  [2];  [2];  [3];  [4];  [1];  [5];  [1]
  1. Univ. College London (UCL) (United Kingdom)
  2. Buck Inst. for Research on Aging, Novato, CA (United States)
  3. Newcastle Univ., Newcastle upon Tyne (United Kingdom)
  4. Northumbria Univ., Newcastle upon Tyne (United Kingdom)
  5. 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. 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, and Akbar, Arne N. Mon . "Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition". United States. doi: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}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 3 works
Citation information provided by
Web of Science

Save / Share:

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
  • DOI: 10.1038/nature03884

PKC signaling prevents irradiation-induced apoptosis of primary human fibroblasts
journal, February 2013


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
  • DOI: 10.1111/jgs.14969

Identification and characterization of a fibroblast marker: FSP1
journal, July 1995


Cellular senescence mediates fibrotic pulmonary disease
journal, February 2017

  • Schafer, Marissa J.; White, Thomas A.; Iijima, Koji
  • Nature Communications, Vol. 8, Issue 1
  • DOI: 10.1038/ncomms14532

Human NK cells display major phenotypic and functional changes over the life span: Human NK cell features over the life span
journal, April 2010


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
  • DOI: 10.1084/jem.20130783

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
  • DOI: 10.1016/j.micinf.2010.07.011

Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer
journal, April 2012


The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression
journal, January 2010


Human NKG2A overrides NKG2C effector functions to prevent autoreactivity of NK cells
journal, April 2011


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
  • DOI: 10.1002/eji.200324432

The impact of ageing on natural killer cell function and potential consequences for health in older adults
journal, September 2013


KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells
journal, June 2009


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
  • DOI: 10.1038/nature03890

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
  • DOI: 10.1093/gerona/glu057

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
  • DOI: 10.1084/jem.20072525

Senescence of T Lymphocytes: Implications for Enhancing Human Immunity
journal, December 2016


Interactions between HLA-G and HLA-E in Physiological and Pathological Conditions
journal, August 2014


An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA
journal, December 2014


Senescence and aging: Causes, consequences, and therapeutic avenues
journal, November 2017

  • McHugh, Domhnall; Gil, Jesús
  • The Journal of Cell Biology, Vol. 217, Issue 1
  • DOI: 10.1083/jcb.201708092

Nk cell Recognition
journal, April 2005


Aging, Cellular Senescence, and Cancer
journal, February 2013


Enhancing Chemotherapy Efficacy in Pten -Deficient Prostate Tumors by Activating the Senescence-Associated Antitumor Immunity
journal, October 2014


Immune surveillance of senescent cells--biological significance in cancer- and non-cancer pathologies
journal, April 2012


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
  • DOI: 10.1101/gad.290635.116

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
  • DOI: 10.3791/3779

Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E
journal, January 2016


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
  • DOI: 10.1016/j.mad.2005.01.004

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
  • DOI: 10.4161/onci.26491

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
  • DOI: 10.1038/ni.2981

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
  • DOI: 10.1084/jem.20020797

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
  • DOI: 10.1038/nature05529

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
  • DOI: 10.1111/acel.12234

Senescence of Activated Stellate Cells Limits Liver Fibrosis
journal, August 2008


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
  • DOI: 10.1038/nature10599

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
  • DOI: 10.1016/j.jid.2017.05.030

The number of p16INK4a positive cells in human skin reflects biological age: p16INK4a in human skin reflects biological age
journal, June 2012


Naturally occurring p16Ink4a-positive cells shorten healthy lifespan
journal, February 2016

  • Baker, Darren J.; Childs, Bennett G.; Durik, Matej
  • Nature, Vol. 530, Issue 7589
  • DOI: 10.1038/nature16932

Regulation of Ligands for the NKG2D Activating Receptor
journal, March 2013


The role of senescent cells in ageing
journal, May 2014


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
  • DOI: 10.1038/ncb1909

Viral Strategies of Immune Evasion
journal, April 1998


Forging a signature of in vivo senescence
journal, June 2015

  • Sharpless, Norman E.; Sherr, Charles J.
  • Nature Reviews Cancer, Vol. 15, Issue 7
  • DOI: 10.1038/nrc3960

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
  • DOI: 10.3390/ph9020023

Effects of anti-NKG2A antibody administration on leukemia and normal hematopoietic cells
journal, December 2015


Relationship between CD107a expression and cytotoxic activity
journal, January 2009


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
  • DOI: 10.1038/nature10600

NKG2D ligands mediate immunosurveillance of senescent cells
journal, February 2016


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
  • DOI: 10.1038/ncb2784

Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression
journal, October 2016


Effect of age and CMV on NK cell subpopulations
journal, June 2014


Cellular senescence: Immunosurveillance and future immunotherapy
journal, May 2018