Cells become senescent and cease replication in response to damage, a toxic environment, or reaching the Hayflick limit. Such cells near all self-destruct or are destroyed by the immune system. In later life, however, they begin to linger and accumulate. This is an issue, as the secretions of senescent cells are quite harmful when sustained over the long term, producing chronic inflammation and disruption of tissue structure and function. The cells of the immune system are no less subject to the burden of cellular senescence than is the case for any other cell type, in fact arguably more so given that infection results in an aggressive replication of immune cells to meet the challenge, pushing those cells towards the Hayflick limit faster than they can be reinforced by newly created immune cells. Senescent immune cells are likely an important contributing cause of the systemic chronic inflammation of aging, as well as of many age-related conditions.
As we age, we accumulate cells in many organs that exhibit signs of DNA damage, have poor proliferative capacity, and are highly secretory. These cells are senescent, defined as being in a state of cell cycle arrest associated with phenotypic and functional changes. While transient senescence is a beneficial mechanism earlier in life, the accumulation of senescent cells with increasing age leads to organ dysfunction, driving inflammation and may underlie many age-related diseases such as atherosclerosis, osteoarthritis, neurodegenerative diseases, and cirrhosis.
While senescence was first discovered in fibroblasts and extensively worked on in other non-leukocytic cells, it has become increasingly clear that immune cells undergo senescence as well. Within the immune system, the existence of non-proliferative leukocyte populations that have high capacity for biologically active mediator secretion has been recognized for many decades, albeit under a different name. These are the effector T lymphocytes that secrete pro-inflammatory cytokines and cytotoxic granules but do not proliferate after activation. Recent studies show that these cells also harbour DNA damage, short telomeres, low telomerase activity, and engage signalling pathways associated with cellular senescence. Therefore, the terms effector T cells and senescent T cells may be synonymous and refer to the same T cell populations.
The extent of T cell proliferation the acute phase of a viral infection drives T cells to senescence. These cells are still susceptible to apotosis but can persist given sufficient antiapototic cytokines in tissue niches. It can be argued that senescent T cells derive from a subpopulation of effector T cells that do not undergo apoptosis, instead becoming senescent and lingering long term. In this article we discuss data on T cell senescence, how it is regulated and evidence for novel functional attributes of senescent T cells. We discuss an interactive loop between senescent T cells and senescent non-lymphoid cells and conclude that in situations of intense inflammation, senescent cells may damage healthy tissue. While the example for immunopathology induced by senescent cells that we highlight is cutaneous leishmaniasis, this situation of organ damage may apply to other infections, including COVID-19 and also rheumatoid arthritis, where ageing, inflammation and senescent cells are all part of the same equation.