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 and Arne N. Akbar ()
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Branca I. Pereira: University College London
Oliver P. Devine: University College London
Milica Vukmanovic-Stejic: University College London
Emma S. Chambers: University College London
Priya Subramanian: University College London
Neil Patel: University College London
Alex Virasami: Great Ormond Street Hospital for Children, University College London
Neil J. Sebire: Great Ormond Street Hospital for Children, University College London
Veronica Kinsler: Great Ormond Street Hospital for Children, University College London
Alexis Valdovinos: Buck Institute for Research on Aging
Claude Jourdan LeSaux: Buck Institute for Research on Aging
João F. Passos: Institute for Cell and Molecular Biosciences & Newcastle University Institute for Ageing
Antony Antoniou: Faculty of Health and Life Sciences, Northumbria University
Malcom H. A. Rustin: University College London
Judith Campisi: Buck Institute for Research on Aging
Arne N. Akbar: University College London

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10335-5

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