Author: Harper Ling
Artist: Qiwen Liu
Editor: Dina Vafakish Sistani
Why are older people more likely to suffer from chronic inflammation? Why is vaccine efficacy reduced in older people? People might attribute those age-related deteriorations to a simple reason: immunity declines as an individual ages.
But what does declined immunity mean?
Helper and cytotoxic (CD4+ and CD8+, respectively) T cells, both excellent guardians in adaptive immune systems, undergo senescence (the process of ageing). Both activated by antigen-presenting ligands, CD4+ T cells are responsible for interacting with B cells to produce antibodies or secreting cytokines which generate signalling cascades on other cell types to clear the pathogens, while CD8+ T cells directly kill the cells by engulfing pathogens in a process called cytotoxicity. “Senescent” does not necessarily mean less “powerful” or “functional.” Here, it refers to the final stage of T cell differentiation. Compared to less differentiated T cell stages such as central- and effector-memory T cells, several key functional differences of senescent T cells (TEMRA) are: reduced proliferative capacity, reduced specificity, and unexpectedly, greater cytotoxicity. TEMRA is less likely to increase its cell number in response to invading pathogens and less capable to distinguish “self” and “non-self,” but kills more cells. Moreover, TEMRA tends to accumulate more in older individuals than in young people. Hence, immunologists have been driven to unravel phenotypic characteristics and functional roles of TEMRA in ageing.
The expression of specific receptor proteins on immune cell surface membranes enables the cells to carry out specialised functions. Interestingly, senescent helper and cytotoxic T cells (TEMRA CD4+ and CD8+) tend to behave as natural killer (NK) cells instead by upregulating expression of typical NK receptors. NK cells are a type of cytotoxic cell in innate immunity. One of its main cell-destroying mechanisms proceeds via non-specific and antigen-independent release of lytic granules containing perforin and granzymes, which are proteins that can pierce the cell membrane and activate caspase-dependent apoptosis (cell death), respectively. The entire process of releasing perforin and granzymes is called degranulation. By assessing gene expression, Pereira et al. found that, compared to non-senescent CD8+ T cells, CD8+ TEMRA gene expression of T cell receptors (which bind to antigen-presenting ligands) were decreased whereas genes of NK receptors (NKRs) and genes involved in NK cell cytotoxic pathway were elevated. Since each type of immune cell expresses a particular set of receptors that act as useful markers for identifying cell type and analysing cellular behaviour, looking into marker expression of TEMRA is fundamental for later cell function studies to further explore how genetic changes affect cellular functions. One widely used method is flow cytometry, which revealed that TEMRA CD8+ T cells express a significant number of NKRs, including degranulation marker CD107a, which is a NK-cell protein suggested to protect itself from damages by perforin and granzymes. Ongoing research held by Luciana Covre et al at the Akbar Lab at UCL cocultured CD8+ TEMRA with fibroblasts (connective tissue cells) and looked into the killing effect, which indicated that CD8+ TEMRA did profoundly kill cells in NK-cell-mediated manner. Later studies have shown that CD4+ TEMRA cells also carry the same transformation. This finding is astonishing, as the paradigm of CD4+ T cells is no longer restrained to those “helper” functions outlined above, and somewhat carries “killer” roles, recognising antigen-presenting cells, activating cytotoxic cells, and introducing immune memory.
Pathways inducing immunosenescence have attracted great interest amongst immunologists; particularly, one sestrin-dependent pathway is well-established. Lanna et al suggested that T cell senescence can be induced by activation of sestrin, a stress-sensing protein. Active sestrin binds to three groups of MAPK proteins (a type of protein kinase), Erk, Jnk, and p38, forming a sestrin-dependent MAPK activation complex (sMAC). When sMAC is activated, Erk, Jnk, and p38 each boost distinct aspects of senescent T cells, such as increased DNA damage, decreased expression of T cell receptor components, and reduced telomerase activity. Therefore, it has been proposed that immunosenescence can be reversed by inhibiting sMAC, a potential pharmaceutical target.
Why bother to reverse immunosenescence? To answer this, we need to look into interactions between senescent T cells and tissue microenvironments. When tissues age, several proinflammatory markers, known as senescence-associated secretory phenotypes (SASPs), are released. The pool of SASPs is postulated to induce expression of both NKR in TEMRA cells and NK ligands in tissues. TEMRA cells begin to indiscriminately destroy any tissue cells that express NK ligands. Moreover, the killing from TEMRA cells further secrete more SASPs, accumulation of which can recruit other immune cells and lead to chronic inflammation. This is unfortunately a vicious loop, which eventually results in high level of proinflammatory markers in blood and tissue microenvironment, a phenomenon called inflammaging. Plentiful evidence suggests that inflammaging is a strong risk factor for various age-related diseases, such as cardiovascular diseases, cancer, dementia, and chronic kidney disease. However, the pathology remains unclear.
Senescent T cells undergo changes and form a destructive inflammatory burden in ageing individuals, despite their capability of eliminating senescent non-immune and cancerous cells to mitigate tissue damage and malignancy, respectively. Reversing T cell senescence remains a challenge,and the pathological roles of the “fallen angels” in age-related diseases are yet to be elucidated. The proposed pathway of sMAC formation suggests that sestrin and MAPK proteins can be potential pharmaceutical targets to reverse T-cell senescence and relieve inflammaging.
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