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. 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}
}
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