As humans live longer, a central concern is to find ways to maintain their health as they age. Immunity declines during ageing, as shown by the increased susceptibility to infection by both ...previously encountered and new pathogens and by the decreased efficacy of vaccination. It is therefore crucial to understand the mechanisms responsible for this decrease in immunity and to develop new strategies to enhance immune function in older humans. We discuss here how the induction of senescence alters leukocyte, and specifically T cell, function. An emerging concept is that senescence and nutrient sensing-signalling pathways within T cells converge to regulate functional responses, and the manipulation of these pathways may offer new ways to enhance immunity during ageing.
In T lymphocytes, the mitogen-activated protein kinase (MAPK) p38 regulates pleiotropic functions and is activated by canonical MAPK signaling or the alternative activation pathway downstream of the ...T cell antigen receptor (TCR). Here we found that senescent human T cells lacked the canonical and alternative pathways for the activation of p38 but spontaneously engaged the metabolic master regulator AMPK to trigger recruitment of p38 to the scaffold protein TAB1, which caused autophosphorylation of p38. Signaling via this pathway inhibited telomerase activity, T cell proliferation and the expression of key components of the TCR signalosome. Our findings identify a previously unrecognized mode for the activation of p38 in T cells driven by intracellular changes such as low-nutrient and DNA-damage signaling (an 'intrasensory' pathway). The proliferative defect of senescent T cells was reversed by blockade of AMPK-TAB1-dependent activation of p38.
One of the most appreciated consequences of immunosenescence is an impaired response to vaccines with advanced age. While most studies report impaired antibody responses in older adults as a ...correlate of vaccine efficacy, it is now widely appreciated that this may fail to identify important changes occurring in the immune system with age that may affect vaccine efficacy. The impact of immunosenescence on vaccination goes beyond the defects on antibody responses as T cell-mediated responses are reshaped during aging and certainly affect vaccination. Likewise, age-related changes in the innate immune system may have important consequences on antigen presentation and priming of adaptive immune responses. Importantly, a low-level chronic inflammatory status known as inflammaging has been shown to inhibit immune responses to vaccination and pharmacological strategies aiming at blocking baseline inflammation can be potentially used to boost vaccine responses. Yet current strategies aiming at improving immunogenicity in the elderly have mainly focused on the use of adjuvants to promote local inflammation. More research is needed to understand the role of inflammation in vaccine responses and to reconcile these seemingly paradoxical observations. Alternative approaches to improve vaccine responses in the elderly include the use of higher vaccine doses or alternative routes of vaccination showing only limited benefits. This review will explore novel targets and potential new strategies for enhancing vaccine responses in older adults, including the use of anti-inflammatory drugs and immunomodulators.
Can the immune system be reactivated continuously throughout the lifetime of an organism or is there a finite point at which repeated antigenic challenge leads to the loss of lymphocyte function or ...the cells themselves or both? Replicative senescence and exhaustion are processes that control T cell proliferative activity and function; however, there is considerable confusion over the relationship between these two intrinsic cellular control mechanisms. In this Opinion article, we compare the molecular regulation of senescence and exhaustion in T cells. Available data suggest that both processes are regulated independently of each other and that it may be safer to block exhaustion than senescence to enhance immunity.
Aging is a global burden, and the increase in life span does not increase in parallel with health span. Therefore, older adults are currently living longer with chronic diseases, increased ...infections, and cancer. A characteristic of aging is the presence of chronic low-grade inflammation that is characterized by elevated concentrations of IL-6, TNF-α, and C-reactive protein, which has been termed inflammaging. Previous studies have demonstrated that chronic inflammation interferes with T-cell response and macrophage function and is also detrimental for vaccine responses. This raises the question of whether therapeutic strategies that reduce inflammation may be useful for improving immunity in older adults. In this review we discuss the potential causes of inflammaging, the cellular source of the inflammatory mediators, and the mechanisms by which inflammation may inhibit immunity. Finally, we describe existing interventions that target inflammation that have been used to enhance immunity during aging.
Aging is associated with profound changes in the human immune system, a phenomenon referred to as immunosenescence. This complex immune remodeling affects the adaptive immune system and the CD8
T ...cell compartment in particular, leading to the accumulation of terminally differentiated T cells, which can rapidly exert their effector functions at the expenses of a limited proliferative potential. In this review, we will discuss evidence suggesting that senescent αβCD8
T cells acquire the hallmarks of innate-like T cells and use recently acquired NK cell receptors as an alternative mechanism to mediate rapid effector functions. These cells concomitantly lose expression of co-stimulatory receptors and exhibit decreased T cell receptor signaling, suggesting a functional shift away from antigen-specific activation. The convergence of innate and adaptive features in senescent T cells challenges the classic division between innate and adaptive immune systems. Innate-like T cells are particularly important for stress and tumor surveillance, and we propose a new role for these cells in aging, where the acquisition of innate-like functions may represent a beneficial adaptation to an increased burden of malignancy with age, although it may also pose a higher risk of autoimmune disorders.
The accumulation of CD28− T cells, particularly within the CD8 subset, is one of the most prominent changes during T-cell homeostasis and function associated with aging in humans. CD28, a major ...co-stimulatory receptor, is responsible for the optimal antigen-mediated T-cell activation, proliferation and survival of T cells. CD28− T cells exhibit reduced antigen receptor diversity, defective antigen-induced proliferation and a shorter replicative lifespan while showing enhanced cytotoxicity and regulatory functions. Gene expression analyses reveal profound changes of CD28− T cells in comparison to their CD28+ counterparts and corroborate their functional differences. Here we review recent advances in our understanding of CD28− T cells and their role in the age-associated decline of immune function.
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.
Summary
As the thymus involutes during aging, the T‐cell pool has to be maintained by the periodic expansion of preexisting T cells during adulthood. A conundrum is that repeated episodes of ...activation and proliferation drive the differentiation of T cells toward replicative senescence, due to telomere erosion. This review discusses mechanisms that regulate the end‐stage differentiation (senescence) of T cells. Although these cells, within both CD4 and CD8 compartments, lose proliferative activity after antigen‐specific challenge, they acquire innate‐like immune function. While this may confer broad immune protection during aging, these senescent T cells may also cause immunopathology, especially in the context of excessive inflammation in tissue microenvironments.
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