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

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.

doi:10.1038/s41467-019-10335-5

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

Journal Article · Mon Jun 03 00:00:00 EDT 2019 · Nature Communications

DOI:https://doi.org/10.1038/s41467-019-10335-5· OSTI ID:1546687

Pereira, Branca I. ^[1]; Devine, Oliver P. ^[1]; Vukmanovic-Stejic, Milica ^[1];

^[1]; Subramanian, Priya ^[1]; Patel, Neil ^[1];

^[1]; Sebire, Neil J. ^[1]; Kinsler, Veronica ^[1]; Valdovinos, Alexis ^[2]; LeSaux, Claude Jourdan ^[2]; Passos, João F. ^[3]; Antoniou, Antony ^[4]; Rustin, Malcom H. A. ^[1]; Campisi, Judith ^[5]; Akbar, Arne N. ^[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)

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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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1546687

Journal Information:: Nature Communications, Vol. 10, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 204 works

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Compartmentalized cytotoxic immune response leads to distinct pathogenic roles of natural killer and senescent CD8 ⁺ T cells in human cutaneous leishmaniasis Covre, Luciana Polaco; Devine, Oliver Patrick; Garcia de Moura, Renan Immunology, Vol. 159, Issue 4 https://doi.org/10.1111/imm.13173	journal	January 2020
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