Senescent T Cells, Immunosenescence, and T Cell Exhaustion are all Distinct but to Some Degree Overlapping Phenomena

Immunosenescence is a high-level descriptive term for one collection of symptoms that manifest in the aging immune system, largely revolving around a loss of capacity: an inability to respond effectively to pathogens and to clear out damaged and dangerous cells. Cellular senescence on the other hand is a low-level descriptive term for a harmful cell state that appears in increasing numbers with advancing age, disrupting tissue function and contributing to age-related diseases. The evidence to date strongly suggests that senescence as a cellular phenomenon extends to the T cells of the adaptive immune system in later life, though it is not yet clear just how similar this is to the manifestation of senescence as it is observed in other cell types, or the degree to which it contributes to immunosenescence.

To further muddy the waters, T cell senescence is not the same as T cell exhaustion, a separate form of immune cell dysfunction that is also associated with age and immunosenescence. Assigning names in biochemistry is a process of drawing a ragged circle around a collection of measures and markers, and perhaps later, once the systems involved are mapped and understood to a much greater degree, some reconciliation and renaming will take place where the accumulated nomenclature becomes obsolete or overlaps in a confusing manner. That point has yet to be reached here.

The immune system is made up of many different immune cell types, each with its own unique functions, to collectively protect the host against foreign pathogens. T cells comprise around 7-24% of the immune cells and around ~70% of the lymphocytes in human blood. The ability of T cells to proliferate upon antigen stimulation is crucial as it dramatically increases the number of antigen-specific T cells to aid in resolving the infection, otherwise known as clonal expansion. After the resolution of the infection, these T cells undergo apoptosis during the contraction phase to return to the steady state. However, as T cells replicate multiple times due to repeated stimulation with pathogens during a host's lifetime, they further differentiate, lose their proliferation capacity and may reach the stage of replicative senescence.

The inability of T cells to proliferate is partly due to the erosion of telomeres and the loss of telomerase activity, a phenomenon is analogous to the Hayflick Limit first characterized in fibroblasts. Besides having an impaired proliferative capacity and shorter telomere length, senescent fibroblasts also adopt a pro-inflammatory profile, whereby they could secrete pro-inflammatory cytokines into the environment and cause tissue damage by chronic inflammation. However, these features of senescence are only established in other cell types, and classical T cells may shares similar features but the signals and pathways leading to those functional hallmarks may be different. Whether cellular senescence shares common pathways across all immune cells and all mammalian cells still needs to be demonstrated.

It is not surprising that investigators are often confused with the terms senescence and exhaustion of T cells. Senescence and exhausted T cells do have some similarity in certain aspects of functionality but they are not entirely the same. Therefore, it is important to note the differences between senescence and exhaustion of T cells, as this will allow accurate interpretation of results and propose the right therapeutic approach to be used. First, the markers expressed by senescent T cells are markers such as CD57 and KLRG-1, which indicates replicative senescent. On the other hand, the markers associated with exhaustion of T cells are programmed cell death 1 (PD-1), lymphocyte activation gene 3 (LAG-3), T cell immunoglobulin mucin 3 (TIM-3) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4).

Second, senescent T cells adopt a pro-inflammatory profile and are able to secrete high levels of pro-inflammatory cytokines with stimulation which is similar to the senescence associated secreting phenotype (SASP) observed in other senescent cell types. The SASP concept has been established in non-immune cells but it remains to be proven in T cells. However, as SASP cells are unable to proliferate but can produce a higher range of pro-inflammatory molecules, it is likely that senescent T cells exhibit some aspects of SASP. Exhausted T cells are unable to both proliferate and to secrete cytokine upon stimulation suggesting again that the two definitions refer to different cellular status.

Third, senescent T cells are more prevalent in the highly-differentiated phenotypes (effector memory/terminal effector) and resistant to apoptosis. Exhausted T cells on the other hand, are usually central memory/effector memory T cells that have undergone repetitive or chronic stimulation. They are programmed to undergo apoptosis as PD-1 pathway seems to strongly associate with survival. Lastly, replicative senescent seems to be irreversible whereas exhaustion is reversible. Studies have shown that blockade of PD-1 ligation is able to recover the function of cytokine secretion in T cells. "Reversing exhaustion" has been very successful in human clinical trials, raising the 5-year survival rate of different type of cancer patients in advanced cancer stages.

Senescent T cells were recently shown to regain function by inhibiting the p38 mitogen-activated protein kinase (MAPK) pathway. Restoring function of senescent T cells is very relevant in the context of human aging while restoring the function of exhausted T cells is more relevant in a pathological context (e.g., cancer immunotherapy, infectious diseases). Having clarified the differences between senescent and exhausted T cells, the markers associated with each phenotype could be co-expressed on the surface of the T cells, which means they could be both senescent and exhausted. It is not clear, however, whether senescent T cells are more susceptible to exhaustion and vice-versa.



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