Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition

Branca I. Pereira; Oliver P. Devine; Milica Vukmanovic-Stejic; Emma S. Chambers; Priya Subramanian; Neil Patel; Alex Virasami; Neil J. Sebire; Veronica Kinsler; Alexis Valdovinos; Claude Jourdan LeSaux; João F. Passos; Antony Antoniou; Malcom H.A. Rustin; Judith Campisi; Arne N. Akbar

doi:10.1038/s41467-019-10335-5

Senescent cells evade immune clearance via HLA-E-mediated NK and CD8⁺ T cell inhibition

Branca I. Pereira, Oliver P. Devine, Milica Vukmanovic-Stejic, Emma S. Chambers, Priya Subramanian, Neil Patel, Alex Virasami, Neil J. Sebire, Veronica Kinsler, Alexis Valdovinos, Claude Jourdan LeSaux, João F. Passos, Antony Antoniou, Malcom H.A. Rustin, Judith Campisi, Arne N. Akbar

Physiology & Biomedical Engineering

Research output: Contribution to journal › Article › peer-review

76 Scopus citations

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.

Original language	English (US)
Article number	2387
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10335-5
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Pereira, B. I., Devine, O. P., Vukmanovic-Stejic, M., Chambers, E. S., Subramanian, P., Patel, N., Virasami, A., Sebire, N. J., Kinsler, V., Valdovinos, A., LeSaux, C. J., Passos, J. F., Antoniou, A., Rustin, M. H. A., Campisi, J., & Akbar, A. N. (2019). Senescent cells evade immune clearance via HLA-E-mediated NK and CD8⁺ T cell inhibition. Nature communications, 10(1), Article 2387. https://doi.org/10.1038/s41467-019-10335-5

Pereira, BI, Devine, OP, Vukmanovic-Stejic, M, Chambers, ES, Subramanian, P, Patel, N, Virasami, A, Sebire, NJ, Kinsler, V, Valdovinos, A, LeSaux, CJ, Passos, JF, Antoniou, A, Rustin, MHA, Campisi, J & Akbar, AN 2019, 'Senescent cells evade immune clearance via HLA-E-mediated NK and CD8⁺ T cell inhibition', Nature communications, vol. 10, no. 1, 2387. https://doi.org/10.1038/s41467-019-10335-5

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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.",

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AU - Subramanian, Priya

AU - Patel, Neil

AU - Virasami, Alex

AU - Sebire, Neil J.

AU - Kinsler, Veronica

AU - Valdovinos, Alexis

AU - LeSaux, Claude Jourdan

AU - Passos, João F.

AU - Antoniou, Antony

AU - Rustin, Malcom H.A.

AU - Campisi, Judith

AU - Akbar, Arne N.

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N2 - 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.

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Senescent cells evade immune clearance via HLA-E-mediated NK and CD8⁺ T cell inhibition

Abstract

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