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Understanding Why the Immune System Fails to Destroy Lingering Senescent Cells May Lead to New Senolytic Therapies

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Posted 12 June 2019 - 06:32 PM

The accumulation of lingering senescent cells in all tissues is one of the causes of aging. Even in very late life, senescent cells are thought to account for only a few percent at most of all cells in any given tissue, but they cause great disruption to tissue structure and function: chronic inflammation, impaired regeneration, fibrosis, and other unpleasant outcomes. This is accomplished via an as yet incompletely cataloged mix of secreted molecules known as the senescence-associated secretory phenotype, or SASP. Acting via secretions allows a small number of cells to have large effects.

When present for a limited period of time, senescent cells are helpful, a necessary part of wound healing, embryonic development, and suppression of cancer. Cells become senescent in response to the circumstance, the SASP assists in calling in the immune system to help, or in spurring growth, or in instructing nearby cells to also become senescent. Then the senescent cells self-destruct or are destroyed by the immune system once their contribution to the task at hand is complete. It is only when senescent cells linger for the long term that the SASP becomes dangerous, corrosive to tissue function.

Why do some senescent cells fail to self-destruct? Further, while we know that the immune system declines with age, becoming less effective in all of its tasks, why specifically do immune cells fail to identify and destroy some senescent cells? Progress towards more complete and detailed answers these questions may open the door to new classes of senolytic therapy, capable of purging senescent cells from old tissues. While a variety of senolytic treatments are either available or under development, none are capable of destroying more than about half at best of these cells, and then only in some tissues. Combinations of different therapies, and more efficient therapies will be needed in the years ahead.

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

Cellular senescence is an evolutionarily conserved mechanism with beneficial effects on tumour suppression, wound healing and tissue regeneration. During ageing, however, senescent cells accumulate in tissues and manifest deleterious effects, as they secrete numerous pro-inflammatory mediators as part of a senescence-associated secretory phenotype (SASP). The elimination of senescent cells in mouse models was shown sufficient to delay the onset or severity of several age-related phenotypes. This has prompted the development of senolytic drugs that selectively target senescent cells. Despite successful reversal of age-related pathologies in animal models, the use of senolytic drugs in humans may be hampered by their lack of specificity for senescent cells, leading to the risk of toxicity. Therefore, alternative approaches that can be used in isolation or in combination with senolytic drugs to improve the elimination of senescent cells in humans should be explored.

Senescent cells can be recognised and eliminated by the immune system. Different immune cell types including macrophages, neutrophils, natural killer (NK) cells and CD4+ T cells have been implicated in the surveillance of senescent cells, depending on the pathophysiological contex. Senescent cells become immunogenic by expressing stimulatory ligands like MICA/MICB that bind to NKG2D and activate their killing by NK cells. Moreover, by secreting chemokines and cytokines, senescent cells can recruit immune cells into tissues that enable senescent cell clearance. However, this secretory process may perpetuate a low-level chronic inflammatory state that underlies many age-related diseases.

Despite the evidence for senescent cell clearance by the immune system, it is not yet clear why senescent cells accumulate during ageing and persist at sites of age-related pathologies. A decline in immune function may contribute to incomplete elimination of senescent cells with age. Ageing has a great impact in both innate and adaptive immune systems, a process known as immunosenescence. Alternatively, changes in major histocompatibility complex (MHC) expression can lead to escape from recognition by the immune system as previously described in cancer and virally infected cells in vivo. Nevertheless, the effects of senescence on MHC expression are not fully understood.

Here, we show that senescent primary human dermal fibroblasts express increased levels of the non-classical MHC-class Ib molecule HLA-E. HLA-E inhibits immune responses against senescent cells by interacting with the inhibitory receptor NKG2A expressed on NK and highly differentiated CD8+ T cells. Accordingly, we find an increased frequency of HLA-E expressing senescent cells in the skin of old compared with young subjects. HLA-E expression is induced by SASP-related pro-inflammatory cytokines, in particular IL-6 and regulated by p38 signalling in vitro. Lastly, we show that that blocking HLA-E/NKG2A interactions in cell culture enhances NK and CD8+ T cell-mediated cytotoxicity against senescent cells. Taken together, these findings suggest that HLA-E expression contributes to the persistence of senescent cells in tissues. HLA-E may therefore represent a novel target for the therapeutic elimination of senescent cells in age-related diseases.

View the full article at FightAging

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