1. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8 + T cell inhibition.
- Author
-
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, and Akbar AN
- Subjects
- Adult, Aged, Aging pathology, Cytokines immunology, Dermis cytology, Fibroblasts pathology, Humans, In Vitro Techniques, Nevus, Pigmented congenital, Nevus, Pigmented immunology, Nevus, Pigmented pathology, Phenotype, RNA, Small Interfering, Signal Transduction, Skin immunology, Skin pathology, Young Adult, p38 Mitogen-Activated Protein Kinases immunology, HLA-E Antigens, Aging immunology, CD8-Positive T-Lymphocytes immunology, Cellular Senescence immunology, Fibroblasts immunology, Histocompatibility Antigens Class I immunology, Killer Cells, Natural immunology, NK Cell Lectin-Like Receptor Subfamily C immunology
- 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.- Published
- 2019
- Full Text
- View/download PDF