The Impact of T-cell Aging on Alloimmunity and Inflammaging

Aging affects immunity broadly through changes caused by immunosenescence, clinically resulting in augmented susceptibility to infections, autoimmunity, and cancer. The most striking alterations associated with immunosenescence have been observed in the T-cell compartment with a significant shift toward a terminally differentiated memory phenotype taking on features of innate immune cells. At the same time, cellular senescence impairs T-cell activation, proliferation, and effector functions, compromising the effectiveness of immunity. In clinical transplantation, T-cell immunosenescence has been the main driver of less frequent acute rejections in older transplant recipients. This patient population, at the same time, suffers more frequently from the side effects of immunosuppressive therapy including higher rates of infections, malignancies, and chronic allograft failure. T-cell senescence has also been identified as an instigator of age-specific organ dysfunction through a process that has been coined “inflammaging,” accelerating organ injury and potentially contributing to the limited lifetime of organ transplants. Here, we provide a summary of the latest evidence on molecular characteristics of T-cell senescence affecting alloimmunity and organ quality while dissecting the consequences of unspecific organ injury and immunosuppression on T-cell senescence. Rather than conceptualizing immunosenescence as a broad and general “weaker” alloimmune response, it appears critical to understand both mechanisms and clinical effects in detail as a basis to refine treatment.


INTRODUCTION
Immunosenescence impacts all cellular immune compartments.The most prominent effects have been observed in the adaptive immune system, whereas components of the innate immune system appear relatively preserved. 1,2mmunosenescence affects both T-and B-cell responses.Age-specific humoral immune responses are clinically evident with impaired responses toward vaccinations in older individuals because of compromised antibody-producing B cells. 3 Underlying molecular mechanisms driving humoral immunity in aging are less well understood.Molecular mechanisms of immunosenescence affecting cellular immunity through alterations of CD4 + and CD8 + T-cell lineages have been analyzed in more detail. 2,4,5T-cell immunity in aging is characterized by both impairments of T-cell function and an altered composition of T-cell subsets that limit the capacity to respond to antigens, thus compromising the effectivity of immune responses. 4][8] Iske et al A large cohort clinical study in approximately 140 000 kidney transplant recipients listed in the Organ Procurement and Transplantation Network database identified recipient age as the strongest risk factor for rejections during the first year after transplantation with less frequent acute rejections in older transplant recipients. 9t the same time, higher mortality rates as a consequence of severe infections have been observed in older transplant recipients, 7,[10][11][12] whereas side effects of established immunosuppressants including posttransplant diabetes and calcineurin inhibitor (CNI)-related nephrotoxicity are more frequent in part linked to altered pharmacodynamics. 13,14Of additional relevance, older transplant recipients have also shown an independently increased risk of chronic allograft loss. 15End-stage organ failure itself has also been recognized as a driver of chronic inflammatory processes.Patients with end-stage renal disease, for example, have shown elevated systemic inflammatory markers that may further accelerate immunosenescence and aging while augmenting rates of frailty. 16At the same time, older diseased organs are more prone to ischemia-reperfusion injury linked to an augmented release of proinflammatory factors. 17he United States Renal Data System database analyzed in an age-stratified manner demonstrated an exponentially increased mortality risk caused by infections in older transplant recipients. 18Noteworthy, noncompliance to immunosuppression may also play a role in older transplant recipients confounding the effects of aging on alloimmunity. 19mmunosenescence affects not only alloimmune responses of transplant recipients but also organ quality and function. 20Recently, an age-specific secretome of senescent T cells termed the senescence-associated secretory phenotype (SASP) has been identified as a driver of age-related organ dysfunction, promoting chronic tissue inflammation. 21This process termed inflammaging may also affect immunogenicity and consequently aggravate alloimmunity.
Thus, an improved understanding of molecular processes and characteristics of T-cell senescence driving compromised alloimmune responses and augmented susceptibilities to the side effects of immunosuppression may help to tailor current established immunosuppressive treatments while facilitating the identification of novel targets enabling age-specific immunosuppression.At the same time, it appears relevant to delineate the impact of T-cell senescence on organ quality and immunogenicity with the clinical goal to increase the utilization of older organs for transplant while improving outcomes when using those organs.

PHENOTYPIC FEATURES OF AGING T CELLS
Life-long antigen stimulation results in terminal differentiation of T cells leading to an advanced cellular dysfunction.Clinical data have shown that the number of naive CCR7 + CD45RA + T cells declines, whereas the number of terminally differentiated CCR7 -CD45RO + memory T cells increases gradually with aging. 22,23Notably, this memory T-cell population is characterized by a distinct phenotype with a changing surface marker expression affecting their function.
At birth, virtually all human T cells express CD28, a key costimulatory receptor, critical for T-cell activation through the T-cell receptor (TCR), affecting proliferation and survival. 24However, by age 80, 10% to 15% of CD4 + and 50% to 60% of CD8 + T cells lack the expression of CD28. 25 Notably, the loss of CD28 with aging has been conceptualized as a result of repeated antigenic stimulation, particularly through persistent viral infections and reactivations including cytomegalovirus (CMV) infections. 26In support, downregulation of CD28 expression in human T cells can be instigated in clinical ex vivo experiments through intermittent antigen stimulation. 27,28D28 − T cells represent a heterogenous population and can be further divided into different subsets characterized by the expression of CD27, CD57, and CD45RO. 29,30In the CD8 + T-cell compartment, the CD28 − CD27 − subset is considered to be close to terminal differentiation. 31ndeed, in parallel to the loss of CD28, human T cells have been shown to augment the expression of CD57 during later stages of T-cell differentiation, events that have been confirmed as a distinct characteristic of replicative senescence. 32,33Correspondingly, augmented CD57 expression has also been attributed to recurrent viral (CMV) infections. 34D4 + T cells from older human individuals have also been characterized by an augmented de novo expression of cytotoxic natural killer (NK) cell receptors, including KIR2DL2 (CD158B1), KIR3DL2 (CD158K), KLRD1 (CD94), KLRF1, KLRK1 (NKG2D), NCR1 (CD355), and CD244 (2B4), 35 reflecting a differentiation toward an innate immune phenotype. 36As observed in CD4 + T cells, old CD8 + T cells have also been shown clinically to exhibit increased levels of activating killer-cell lectin-like receptors and killer-cell immunoglobulin-like receptors. 37onsistent with the downregulation of CD28, increased NK cell receptor expression has been linked to recurrent antigenic TCR stimulation 38 constituting an alternative and compensatory pathway of the classical TCR/CD28 activation in human CD8 + T cells. 39ost recently it has also been shown that old T cells exhibit a broad range of characteristics otherwise seen in senescent somatic cells indicating that both aging processes and differentiation into a memory phenotype are operative.Along those lines, increasing amounts of senescence-associated β-galactosidase (sa-β-gal) activity have been identified in T cells from older individuals throughout all differentiation states, a process that has also been characterized by an augmented p16 expression, a cyclindependent kinase inhibitor mediating cell cycle arrest. 40hese observations had been most prominent in the CD8 + T cells compartment with elevated sa-β-gal activity levels (64%) in individuals aged >60 y. 40 Notably, sa-β-gal expression had been observed independently of the differentiation state indicating that both naive and memory T cells are significantly impacted by the aging environment, thus becoming senescent. 40Likewise, old human naive and memory T cells have shown gene expression signatures characteristic of cellular senescence that are otherwise observed in human fibroblasts. 40Moreover, old human CD28 -CD57 + T cells not only have short telomeres but also compromised telomerase activity together with signs of DNA damage, including yH2AX foci, typical features of senescent somatic cells. 32,41,42In parallel, old human T cells were found to exhibit further characteristics of senescent somatic cells exhibiting a substantial resistance toward apoptosis in addition to an SASP and an augmented MAPK signaling. 43However, T cells from older humans contain abundant amounts of mitochondrial proteins with impaired oxidative phosphorylation, suggesting that dysfunctional mitochondria accumulate, probably due to their inefficient recycling by autophagy. 44ollectively, these molecular characteristics translate into a broad range of impaired functions of old T cells, including a limited proliferative capacity, abrogated TCR signaling, and an altered cytokine expression in addition to a significant limitation of the T-cell subset distribution.These changes appear critical for the observed age-specific dysfunctions in immunity.In clinical transplantation, those changes lead to compromised (allo)immunity with augmented side effects and more frequent chronic allograft dysfunction.

FUNCTIONAL FEATURES OF T-CELL AGING IN ORGAN TRANSPLANTATION
Adoptively transferred naive old but not young murine CD4 + T cells have shown a significantly diminished proliferation. 45Mechanistically, those old CD4 + have shown a diminished capacity to express interleukin (IL)-2, critical for clonal expansion of activated T cells.Of interest, exogenous IL-2 administered in vitro to cultured murine CD4 + T cells restored proliferation in an age-independent manner. 45Consistent with the observation in the CD4 + T-cell compartment, several clinical and experimental studies have also shown that naive old CD8 + T cells have an intrinsic limitation for proliferation and cytokine production. 46ith aging, metabolic alterations become obvious in T cells.The accumulation of dysfunctional mitochondria with compromised oxidative phosphorylation (OXPHOS) and glycolytic pathways has been identified as an underlying mechanism for the observed compromised proliferative capacity.In detail, both murine and human old naive T cells revealed a significant reduction in basal respiration and maximal respiratory capacity on activation indicating an impaired OXPHOS.At the same time, extracellular acidification rates (a measure of glycolysis) have also been inferior. 47Mechanistically, a compromised expression of OXPHOS genes has been observed in both old human CD4 + and CD8 + T cells 44,48 with a reduced capacity for NRF1 to maintain the activity of OXPHOS gene promoters. 48Moreover, defective mitochondrial turnover by autophagy may impair glycolysis.Notably, old human CD4 + T cells have been shown to exhibit increased numbers of autophagosomes with augmented levels of ETC proteins compromising glycolysis. 44Additionally, old murine T cells have a significantly impaired 1-carbon metabolism, 49 crucial for T-cell proliferation and survival. 50This compromised 1-carbon metabolism was partly reversed on formate and glycine supplementation during activation. 49f additional relevance, a compromised CA 2+ influx has been identified in old murine T cells. 51ld naive CD4 + T cells are characterized by a severely compromised responsiveness toward antigen-presenting cells (APCs).Old murine CD4 + T cells formed significantly fewer immunological synapses with APCs 52 and exhibited an attenuated activation characterized by altered cytoskeletal rearrangement preventing the migration of protein kinases and their substrates to the TCR/APC interface. 53Similarly, gene profiling of old, murine CD8 + T cells demonstrated a reduced chemokine ligand-3 and CD40L expression playing a critical role in the APC-T cell interactions. 54Moreover, naive old murine CD4 + T cells display augmented apoptosis when activated with anti-CD3 and anti-CD28 antibodies in vitro, 55 contributing to a further attenuation of effector immune responses.
Old CD4 + T cells stimulated with allo-antigens 47 have also shown an impaired IL-2 production, resulting in a restrained proliferation that may dampen alloimmunity (Figure 1).
Notably, not only naive but also senescent memory T cells exhibit a compromised proliferation on activation with a limited expression of IL-2 because the progressive downregulation of CD28 in older T cells constitutes a crucial costimulatory signal during T-cell activation. 56oreover, effector memory T cells generated from old murine naive CD4 + T cells display a reduced expression of differentiation and activation markers including CD25 and CD62 57 further constraining the activation potential of these cells.In addition to a limited expression of activation markers, both senescent murine and human T cells concomitantly display an increased expression of inhibitory receptors including programmed cell death 1, cytotoxic T-lymphocyte antigen 4 (CTLA4), and lymphocyte activation gene 3, all inhibiting TCR signaling pathways 58 (Figure 2).
Aging goes along with a limited TCR repertoire with T-cell diversity dropping 1000-fold in individuals aged >70 y, 59,60 a process that is primarily attributed to the decline in naive T cells that have not experienced antigen stimulation yet. 61,62A rising number of terminally differentiated memory T cells represents an additional characteristic feature in aging. 63On a cellular level, an age-dependent decline in miR-181a, which regulates intrinsic TCR signaling, 64 has been observed in old human CD4 + T cells associated with an impaired TCR sensitivity in old CD4 + T cells induced through an augmented dual-specific phosphatase 6 activation. 65Experimentally, the accumulation of a distinct population of antigen-naive but semidifferentiated so-called virtual memory T cells (CD44 hi CD49d lo ) with restricted proliferative and functional capacities have been characterized as a major reason for the proliferative and functional deficits of the naive T-cell compartment in old mice.At the same time, proliferative and functional aptitudes of true naive T cells (CD44 lo ) have been preserved. 62Notably, virtual memory T cells have transcriptional and functional characteristics of senescence including an enhanced expression of cyclin dependent Kinase inhibitors, impaired accumulation cyclin D1, and dysregulated MAPK signaling. 62verall, these observations support the concept of dichotomous mechanisms, including cell intrinsic T-cell senescence as well as altered subset compositions driving immunosenescence, overall resulting in an age-specific alloimmunity.

THE IMPACT OF T-CELL AGING ON ORGAN FUNCTION
][68][69] Iske et al We have recently reported that augmented frequencies of senescent cells in murine donor organs promote alloimmune responses through an augmented release of SASP factors that include cell-free mitochondrial DNA. 70Notably, not only senescent somatic cells but also senescent T cells may impair outcomes when transplanting older organs initiating augmented alloimmune responses.Those changes may at the same time also constrain organ function through the induction of inflammaging.Indeed, senescent human T cells have been shown to exhibit compromised proliferative capacities while acquiring a proinflammatory phenotype with an augmented expression of NKG2D associated with interferon (IFN)-γ and granzyme secretion communicated through sestrin signaling. 71Consistently, old murine kidney transplants have harbored significantly higher frequencies of memory T cells with a senescent phenotype characterized by an upregulated NKG2D expression in addition to an augmented SASP and IFN-γ production.The accumulation of senescent T cells in old organs has furthermore been linked to a proinflammatory response within the graft while promoting distinct recipient alloimmune responses in mice. 72Applying senolytics (ABT-263) that deplete senescent cells dampened organ inflammation and restrained Th1-driven alloimmune responses. 72oreover, single-cell RNA and antigen receptor sequencing in various murine organs revealed a subpopulation of age-associated granzyme K (GZMK) expressing CD8 + memory T cells that had been distinct from classic T effector memory cells.Strikingly, these cells have been shown to produce enhanced SASP amounts including the release of IL-6, chemokine (C-C motif) ligand 5, chemokine (C-C motif) ligand 2, and chemokine (C-X-C motif) ligand 1 from nonsenescent stroma cells through secretion of GZMK in various tissues. 73Furthermore, circulating human GZMK + CD8 + T cells with similar transcriptional and epigenetic signatures as their murine counterparts accumulate in older individuals correlating with plasma levels of elevated inflammatory SASP factors, including IL-6, tumor necrosis factor-α, and IL-8, 73 all established mediators of organ inflammaging and tissue dysfunction. 74f additional relevance, human aging also correlated with an increased CD8 + T cell-derived production of mitochondrial reactive oxygen species, 75 further promoting cellular senescence through SASP induction. 76echanistically, mitochondrial dysfunction subverts T-cell differentiation to an inflammatory phenotype, thus inducing senescence and causing tissue dysfunction.Imitating age-associated mitochondrial T-cell dysfunction through knockout of the mitochondrial transcription factor A induced a TH1 proinflammatory phenotype in murine T cells with an increased expression of IFNγ, tumor necrosis factor-α, IL-6, and IL-1β, 77 affecting senescence in a broad range of organs with augmented frequencies of senescent cells in livers, hearts, and kidneys. 78trikingly, these processes had been linked to an accelerated "general" aging of mitochondrial transcription factor A-deficient mice with the manifestation of cognitive and physical dysfunction in addition to profound cardiovascular alterations. 78Consistent with the observation of senescent T cell-derived organ inflammation, augmented frequencies of senescent T cells have clinically been linked to myocardial inflammation, 79 heart failure, 80 and overall cardiovascular mortality 81 in addition to renal failure 82 and lung fibrosis as a consequence of viral pneumonia. 83ld tissue-resident T cells residing in donor organs in addition to infiltrating senescent T cells of recipient origin may thus further constrain transplant outcomes through inflammaging and subsequent tissue dysfunction.
Notably, T cells as well as NK cells are furthermore able to recognize and eliminate murine and human senescent cells both in vitro and in vivo. 84,85Of relevance, immunosurveillance appears less effective in aging and may thus pave the way for senescent cell accumulation. 86Indeed, transgenic mice exhibiting a knockout of perforin required for the cytotoxic activity of NK and T cells displayed augmented numbers of senescent cells in a broad range of murine organs associated with physical dysfunction, impaired tissue structure, and compromised life span. 87-cell immunosenescence may thus further contribute to senescent cell accumulation in older organs promoting more pronounced inflammaging while contributing to an accelerated aging process that may, at least in part, drive chronic allograft nephropathy (Figure 3).

THE IMPACT OF TRANSPLANTATION ON T-CELL AGING
Repetitive antigen stimulation, for example, through CMV persistence, is suggested to enhance immunosenescence with higher levels of terminally differentiated memory T cells in the CD4 + and the CD8 + T-cell compartment of CMV-seropositive older transplant recipients. 88herefore, CMV seropositivity has been considered by many as a driver of immunosenescence.Likewise, because transplantation of an allogeneic donor organ exposes the recipient immune system to repetitive antigen stimulation, it has also been suggested that chronic antigen exposure in organ transplantation may accelerate immunosenescence. 89Indeed, it has been demonstrated in a cohort of kidney transplant recipients that T-cell telomere length decreases during the first year after transplantation in parallel to an accumulation of senescent CD57 + CD28 -T cells. 33Of translational relevance, higher frequencies of both senescent CD4 + and CD8 + T cells correlated tightly to infections within the study period. 33Similarly, kidney transplant recipients containing their graft for >10 y without rejection under CNI monotherapy exhibited increased frequencies of senescent CD27 -CD28 -CD45RO + CD8 + T cells with innate-like functional features including the expression of the NK cell receptors panKIR/NKG2a in addition to the property to produce IFN-γ in response to innate-like stimulation with IL-12 or IL-18. 90Strikingly, these cells had been further characterized by an augmented expression of perforin, mediating T cell-derived inflammaging. 90Furthermore, both studies demonstrated that the increase in senescent T cells had been most prominent in CMV-positive transplant recipients. 33,90However, a recent study evaluating the distribution of naive and terminally differentiated senescent T cells in young and old recipients after kidney transplantation identified age as the major driver of a senescent immune phenotype independent of CMV status. 91Interestingly, the frequency of CMVresponsive terminally differentiated CD8 + T cells has been observed to increase after transplantation in seropositive patients even in the absence of CMV disease. 92This process may be mediated by subclinical, controlled viremia, 93 cross-reactivity of CMV-specific T cells with alloantigens and subsequent expansion, 94 or as a consequence of age-specific effects of immunosuppressants on different T-cell subsets. 95Noteworthy, T-cell senescence may also be instigated before transplantation because of end-stage organ failure.In patients having chronic kidney disease, for instance, uremia has been associated with increased frequencies of terminally differentiated CD4 + and CD8 + T cells with a decreased relative telomere length. 96Likewise, studies in pediatric patients with chronic kidney disease have demonstrated T-cell phenotypes with increased CD57 expression and loss of CD28 comparable with those of healthy older individuals. 97onsistent with previous reports, increased frequencies of senescent T cells have been linked to infections within the first year after transplantation. 91hus, analogous to viral infections, chronic antigen exposure after organ transplantation may contribute to immunosenescence with a particular impact on the T-cell compartment that may, in turn, contribute to an increased susceptibility toward infections and higher mortality.

T-CELL AGING AND IMMUNOSUPPRESSION
Clinical trials investigating the efficacy of immunosuppressants have mostly excluded older transplant recipients that frequently display complex comorbidities requiring multidrug treatments. 98In clinical practice, older and younger transplant patients are usually treated with the same immunosuppressants and comparable drug levels. 99owever, this one-size-fits-all approach may not consider age-specific alterations of the immune system or age-specific effects of immunosuppression. 100,101Indeed, several experimental and clinical studies have suggested that similar levels of CNIs exert greater immune suppression in older transplant recipients deriving from altered metabolization through CYP3A5-enzyme complexes. 102,103Similarly, the clearance of prednisolone 104 and methylprednisolone 105 has been shown to decline with aging due to an increased exposure and an augmented adrenal suppression.
Strategies of "just" lowering dosages of established immunosuppressants in older patients have not always been successful with some trials resulting in increased rates of acute rejection. 100,106These observations are linked to diverse interactions of established immunosuppressants particularly with recipient T cells leading to altered effectiveness of immunosuppression in young and old recipients.
Age-dependent metabolic and immunosuppressive effects of tacrolimus for instance have been delineated in a murine transplant model showing prolonged graft survival in old animals.Mechanistic experimental studies have shown that tacrolimus compromised Ca 2+ influx after murine T-cell activation leading to significantly reduced calcineurin concentration in old T cells, thus restraining IL-2 production and T-cell proliferation.Notably, these effects had been limited to the CD4 + T-cell compartment, whereas CD8 + T cells had been spared. 107imilarly, age-specific effects of rapamycin prolonging allograft survival specifically in old mice have been observed.However, these effects had not been mediated through a more prominent suppression of T cells or an altered subset composition but via a significant increase in IFN-γ/IL-10 double-positive regulatory type 1 cells induced by rapamycin specifically. 108dministration of the receptor fusion protein belatacept (CTLA4-Ig), a fusion protein blocking costimulatory signaling between APCs and T cells through CD28, in contrast, caused a significant perturbation of the T-cell compartment in young but not old recipient mice.While reducing the number of CD4 + effector memory T cells with diminished systemic IFN-γ levels in young recipient animals, the T-cell subset composition in old animals remained unaffected and linked to a significant downregulation of CD28 -in senescent CD4 + T cells after transplantation.Regulatory T cells, in contrast, demonstrated an increased expression of CD28 with aging.CTLA4-Ig treatment in old recipients resulted in reduced frequencies, compromised proliferation, and diminished suppressive capacity of regulatory T cells. 109ollectively, these results indicate that immunosuppressive drugs exert diverse and age-specific effects requiring a more profound understanding of the interplay between immunosuppressive regimens and senescent immune cells to dissect parameters for guiding dosing and the choice of immune suppression in older transplant recipients.Recognizing complex medical conditions and addressing this issue, the Food and Drug Administration has endorsed clinical trials in the elderly (GAO-07-47R).Biological rather than chronological age has been considered as a more relevant predictor of how older recipients are likely to fare after transplant with certain immunosuppression regimens including immunosuppression efficacy and side effects. 13Assessing frailty and the consequences on organ transplantation effects 110 while implementing specific tests (Fried's frailty phenotype and Karnofsky Performance Score) 111 may help to better distinguish biological from chronological age.Additionally, modern laboratory tests assessing DNA methylation and biomarkers are able to measure biological age and could support age-adapted immunosuppression. 112

CONCLUSION
Collectively, T-cell senescence constitutes an agedependent phenomenon affecting the functionality of adaptive immunity leading to compromised age-specific alloimmune responses and pathogen defense.T-cell senescence also contributes critically to organ aging.Clearly, age-specific immunosuppression is necessary to optimize outcomes.Understanding mechanisms of age-specific alloimmunity, modes of action of established immunosuppressants, or those that will specifically aim for age-specific targets, ideally supported by age-specific immunoassays, is expected to improve outcomes in older transplant recipients while facilitating the increased utilization of older organs.Indeed, there is a pressing relevance to tackle those most relevant clinical problems with a rapidly growing population of older transplant recipients.

FIGURE 1 .
FIGURE 1. Features of senescent naive T cells affecting age-specific alloimmunity.Proliferating naive T cells display (A) functional telomerase and are activated through (B) TCR signaling (C) on antigen presentation by APCs leading to (D) IL-2 secretion and (E) proliferation.Senescent T cells, in turn, display general characteristics of cellular senescence including (F) telomere-associated foci, (G) sa-β-gal, and (H) p16 expression linked to (I) arrested proliferation.Moreover, senescent T cells exhibit subset-specific features including (J) abrogated TCR signaling due to augmented miR-181a levels, (K) compromised interaction with APCs in addition to (L) diminished IL-2 secretion on activation.These characteristics contribute to age-specific T-cell responses in alloimmunity.APC, antigen-presenting cell; IL-2, interleukin 2; sa-β-gal, senescence-associated β-galactosidase; TCR, T-cell receptor.

FIGURE 2 .
FIGURE 2. Features of senescent memory T cells associated with inflammaging.Memory T cells in young individuals display (A) functional telomerase and are activated through (B) T-cell receptor signaling leading to prominent (C) IL-2 secretion and proliferation.Senescent memory T cells, in turn, display general characteristics of cellular senescence including (D) telomere-associated foci, (E) sa-β-gal, and (F) p16 expression linked to (G) arrested proliferation.Moreover, senescent memory T cells exhibit subset-specific features including (H) the expression of inhibitory molecules, including CTLA4 and PD-1, (I) augmented expression of NK cell receptors, including KIRs, and (L) display an augmented secretion of IFN-γ and granzymes.K, Additionally, senescent memory T cells exhibit a compromised activation with diminished IL-2 and proliferation.These characteristics may promote cellular senescence in transplant recipients and contribute to inflammaging.CTLA4, cytotoxic T-lymphocyte antigen 4; IFN-γ, interferon gamma; IL, interleukin; KIR, killercell immunoglobulin-like receptor; NK, natural killer; PD-1, programmed cell death 1; sa-β-gal, senescence-associated β-galactosidase; SASP, senescence-associated secretory phenotype.

FIGURE 3 .
FIGURE 3. Interplay between senescent T cells and stromal cells.Senescent memory T cells including GZMK expressing CD8 + memory T cells express a variety of proinflammatory factors compiled as the SASP.SASP factors, in turn, are capable of inducing senescence in naive, proliferating stroma cells causing cell cycle arrest and further SASP production.Senolytics including ABT-263 deplete senescent memory T cells and may thus contribute to alleviating inflammaging.GZMK, granzyme K; IL, interleukin; ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype; TNF-α, tumor necrosis factor-alpha.