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

被引：369

作者：

Pereira, Branca I. ^{[1
]}

Devine, Oliver P. ^{[1
]}

Vukmanovic-Stejic, Milica ^{[1
]}

Chambers, Emma S. ^{[1
]}

Subramanian, Priya ^{[1
]}

Patel, Neil ^{[1
]}

Virasami, Alex ^{[2
]}

Sebire, Neil J. ^{[2
]}

Kinsler, Veronica ^{[3
]}

Valdovinos, Alexis ^{[4
]}

LeSaux, Claude Jourdan ^{[4
]}

Passos, Joao F. ^{[5
,6
,7
]}

Antoniou, Antony ^{[8
]}

Rustin, Malcom H. A. ^{[1
]}

Campisi, Judith ^{[4
,9
]}

Akbar, Arne N. ^{[1
]}

机构：

[1] UCL, Div Infect & Immun, London WC1E 6JF, England

[2] UCL, Great Ormond St Hosp Children, Inst Histopathol, London WC1N 3JH, England

[3] UCL, Great Ormond St Hosp Children, Paediat Dermatol Dept, London WC1N 3JH, England

[4] Buck Inst Res Aging, 8001 Redwood Blvd, Novato, CA 94945 USA

[5] Inst Cell & Mol Biosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[6] Newcastle Univ, Inst Ageing, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[7] Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN 55905 USA

[8] Northumbria Univ, Fac Hlth & Life Sci, Dept Appl Sci, Newcastle Upon Tyne NE1 8ST, Tyne & Wear, England

[9] Lawrence Berkeley Natl Lab, 1 Cyclotron Rd, Berkeley, CA 94720 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

英国医学研究理事会; 美国国家卫生研究院; 英国生物技术与生命科学研究理事会;

关键词：

SECRETORY PHENOTYPE; NKG2D LIGANDS; EXPRESSION; SURVEILLANCE; AGE; IMMUNOSURVEILLANCE; CD94/NKG2A; REGULATOR; RESPONSES; CANCER;

D O I：

10.1038/s41467-019-10335-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

共 57 条

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