Naive Maintenance and Function in Human Aging Jörg J. Goronzy, Fengqin Fang, Mary M. Cavanagh, Qian Qi and Cornelia M. Weyand This information is current as of September 26, 2021. J Immunol 2015; 194:4073-4080; ; doi: 10.4049/jimmunol.1500046 http://www.jimmunol.org/content/194/9/4073 Downloaded from

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology

Naive T Cell Maintenance and Function in Human Aging Jo¨rg J. Goronzy, Fengqin Fang, Mary M. Cavanagh, Qian Qi, and Cornelia M. Weyand In studies of immune aging, naive T cells frequently lecular hallmarks that describe common pathways that, in take center stage. Describing the complexity of the hu- turn, signify aging over a range of tissues and species: stem man naive T cell repertoire remains a daunting task; cell exhaustion limiting regenerative capacity; various forms however, emerging data suggest that homeostatic mech- of genomic instability, including telomere attrition, DNA anisms are robust enough to maintain a large and di- damage, mitochondrial dysfunction, and epigenetic changes; verse CD4 T cell repertoire with age. Compartment loss of proteostasis; nutritional sensing; cellular senescence; shrinkage and clonal expansions are challenges for naive and altered intercellular communication (Table I). In this review, we discuss how these general aging mechanisms help CD8 T cells. In addition to population aspects, identi- Downloaded from fication of potentially targetable cellular defects is re- explain age-associated changes in the and, ceiving renewed interest. The last decade has seen conversely, how studies on T cell aging can expand this remarkable progress in identifying genetic and bio- conceptual framework. We focus exclusively on human naive T cells and refer to recent broader reviews for comprehensive chemical pathways that are pertinent for aging in gen- reading on immune aging (10–14). eral and that are instructive to understand naive T cell http://www.jimmunol.org/ dysfunction. One hallmark sets naive T cell aging apart Age and regenerative capacity—maintaining the size of the naive T cell from most other tissues except stem cells: they initiate pool but do not complete differentiation programs toward As pointed out by Lo´pez-Otı´n et al. (9), a decline in regen- memory cells. Maintaining quiescence and avoiding dif- erative capacity is a well-appreciated hallmark of aging, and ferentiation may be the ultimate challenge to maintain attrition of stem cells with age is a universal finding in vir- the functions unique for naive T cells. The Journal of tually all tissues (Table I). To prevent stem cell exhaustion, Immunology, 2015, 194: 4073–4080. mechanisms are in place to preserve cell quiescence (15). Failure of these mechanisms leads to premature exhaustion by guest on September 26, 2021 ging, defined as progressive functional decline over and accelerates the aging process. The adaptive immune sys- time, affects all organ systems and is the major cause tem is special, in that generation of novel naive T cells is A of, or at least contributes to, most diseases in the entirely dependent on thymic function. Because thymic out- adult. The immune system is a prime example; immune put peaks at and progressively declines thereafter, competence declines with age, causing increased morbidity and thymic may be independent of and precede stem mortality from , as well as being a factor in the cell aging. The naive T cell emerges as a quasi–stem cell increased incidence of malignancies (1–3). Less intuitively, the regenerating the T cell system, and principles of stem cell aging immune system is also more inclined to elicit nonspe- aging apply to naive T cell aging. cific inflammation, which accelerates degenerative diseases, The dramatic loss of the prompted a natural sup- most prominently seen in cardiovascular and neurodegener- position that thymic involution is responsible for the age- ative disorders (4–6). Moreover, immune aging can impair associated failure of the (16, 17). tolerance mechanisms and is a risk factor for autoimmunity Indeed, the naive T cell compartment in the mouse is de- (7, 8). Generally known as “,” this term is pendent on thymic emigrants throughout life. Insufficient too narrow to reflect the multitude of mechanisms involved production of new cells by the thymus during aging is asso- and may even be misleading, implying cellular senescence as ciated with compartment shrinkage and eventually leads to the main pathological event. holes in the murine T cell repertoire (18, 19). Several lines of recent evidence have challenged the importance of thymic Hallmarks of aging involution in human immune aging (20). Although vital for To describe our current understanding of the aging process in building a T cell repertoire during the growing phases of its complexity, Lo´pez-Otı´n et al. (9) define cellular and mo- the host, thymic output appears unnecessary for repertoire

Division of Immunology and Rheumatology, Department of Medicine, Stanford Uni- Address correspondence and reprint requests to Dr. Jo¨rg J. Goronzy, Department of versity, Stanford, CA 94305; and Department of Medicine, Veterans Affairs Palo Alto Medicine, Division of Immunology and Rheumatology, Stanford University School of Health Care System, Palo Alto, CA 94306 Medicine, CCSR Building, Room 2225, 269 Campus Drive West, Stanford, CA 94305- 5166. E-mail address: [email protected] Received for publication January 9, 2015. Accepted for publication March 2, 2015. Abbreviations used in this article: IGF, insulin-like growth factor; miRNA, microRNA; This work was supported by National Institutes of Health Grants R01 AR042547, R01 mtDNA, mitochondrial DNA; TREC, TCR excision. HL117913, R01 AI044142, R01 AI108906, and P01 HL058000 (to C.M.W.) and R01 AI108891, R01 AG045779, U19 AI090019, and U19 AI057266 (to J.J.G.). Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500046 4074 BRIEF REVIEWS: AGE AND ADAPTIVE IMMUNITY

Table I. Comparison of pathways pertinent in general aging to findings in T cell aging and differentiation

Hallmarks Associated with Naive T Cell General Aging Hallmarksa Naive T Cell Aging Hallmarks (Human) Activation/Differentiation Decline in regenerative capacity/stem Thymic involution, no evidence for Not applicable cell exhaustion homeostatic proliferation exhaustion Telomeric attrition Telomeric attrition Telomeric attrition Genetic instability/DNA damage Defective DNA repair responses associated Increased DNA damage compared with naive T cells with premature naive T cell aging in rheumatoid arthritis Epigenetic alterations No data Poised effector genes Cellular senescence Inconclusive evidence Induction of p16 with naive T cell activation Metabolic processes/nutrient sensing/ No data Aerobic glycolysis/oxidative phosphorylation pathways strictly insulin-IGF pathway linked with activation/differentiation Mitochondrial dysfunction No data Increased mitochondrial capacity Loss of proteostasis No data in humans, autophagy defects in Autophagy involved in T cell differentiation mouse Loss of stem cellness due to Partial differentiation into memory cells Full differentiation into partial lineage commitment (miRNA expression patterns, expression of memory T cells CD25 and CD95) aModified from Lo´pez-Otı´n et al. (9). Downloaded from maintenance during adulthood, and T cell regeneration is ingly more T cells participate in proliferation and lose CD31 2 nearly entirely derived from homeostatic proliferation of the (33, 34). In parallel, the CD31 naive T cell population existing T cell pool, which is sufficient to maintain a large increases in size and its TREC content more drastically compartment of naive CD4 T cells (Fig. 1) (21). declines (33). The loss of CD31 expression in naive T cells is Surgery removing or reducing the thymus in early childhood generally not associated with the acquisition of phenotypic http://www.jimmunol.org/ changes the composition of the T cell compartment, mim- markers of memory T cells. icking immune aging in young adults, but only in individuals chronically infected with CMV (22). Similarly, the relative expansion of memory and effector T cell populations and the relative decline in naive CD4 T cells, attributed to age in earlier studies, is entirely due to chronic CMV stimulation and not found in older individuals who do not have Abs to CMV (23). More importantly, data on T cell turnover and by guest on September 26, 2021 decline in TCR excision circles (TRECs) best fits to the model that T cell generation in the adult relies mostly, if not entirely, on homeostatic proliferation of existing naive T cells. Despite a decrease in daily thymic output by a factor of 10–100 during adult life, peripheral naive T cell turnover does not measurably increase, suggesting that that peripheral prolifer- ation does not need to compensate for thymic failure and that even in early adulthood, thymic output contributes little to the maintenance of the size of the naive T cell compartment (24– 26). Only in the eighth and ninth decade of life does the fre- quency of cycling cells increase, probably as a consequence of increased cell death rather than lack of thymic function (27, 28). Peripheral expansion of naive T cells is driven by tonic TCR signals and homeostatic cytokines, in particular by IL-7 (29, 30). IL-7 concentrations do not decline with age and therefore do not become limiting, consistent with the observation that the CD4 T cell compartment does not reduce in size. IL-2 stimulation may also play a role because naive CD4 T cells increasingly express the high-affinity IL-2 receptor CD25 with age and become IL-2 responsive (31). IL-7 drives T cell FIGURE 1. Naive T cell homeostasis and age. Thymic T cell regeneration is proliferation without inducing a switch to a memory phe- quantitatively irrelevant throughout adult life, and homeostatic proliferation is notype in vitro (32). CD31, expressed on a subset of naive responsible for maintaining the size of the naive T cell compartment. Although CD4 T cells, identifies recent thymic emigrants or at least only thymic T cell generation can add novel naive T cells and enrich diversity, cells that have not peripherally proliferated. TREC concen- homeostatic T cell proliferation can sustain the richness of the TCR repertoire + (i.e., the total number of T cells with different TCR sequences), whereas peripheral trations decrease slightly in CD31 CD4 T cells with age, selection during homeostatic proliferation may result in increasing unevenness, consistent with only limited replication in this population that is, increasing inequalities in clonal sizes and clonal expansions of selected few + (33). As one would expect, the CD31 population progres- clones. Age-associated changes in these metrics between CD4 and CD8 T cells of sively shrinks with age, consistent with the idea that increas- young (,35 y) and older (65–80 y old) healthy adults are illustrated. The Journal of Immunology 4075

In contrast to CD4 T cells, the naive CD8 T cell com- sequence of increased cell loss rather than defective generation partment shrinks with age (Fig. 1) (23, 35). The reason for (Fig. 1). A lack of regenerative capacity and a decline in this subset difference is unclear. Theoretically, homeostatic immune-competent cells does not appear to cause the im- proliferation conditions are not worse for CD8 T cells. On mune defects in adaptive immune responses, in particular the the contrary, CD8 T cells should receive more signals from CD4 T cell–dependent responses after vaccination. abundant MHC class I than CD4 cells receive from restrict- edly expressed MHC class II molecules. Indeed, compared Age and regenerative capacity—maintaining richness of the naive with CD4 T cells, naive CD8 T cells develop a higher degree T cell pool while avoiding clonality of clonal size inequality with frequent clonal expansions, in- T cell replenishment is unique in that it not only has to dicating that naive CD8 T cells do proliferate at a higher rate maintain compartment size, but also TCR diversity. Unlike in than CD4 T cells (Fig. 1) (36). Shrinking of the naive CD8 B cells, generation of new T cell specificities entirely relies on T cell compartment may therefore not be due to defective thymic production and cannot be accomplished by expansion regeneration. Alternatively, naive CD8 T cells may acquire and modification of naive T cells. For T cell homeostatic phenotypic memory markers due to increased turnover. In mechanisms to maintain a diverse repertoire, at least three murine models, such virtual memory T cells preferentially conditions must be met: 1) the initial clonal size in the naive develop in the CD8 compartment (37, 38). However, TCR T cell compartment must be of sufficient size to confer ro- sequencing studies do not support the notion that develop- bustness to loss of T cells; 2) the initial TCR repertoire must be ment of CD8 virtual memory T cells is a frequent event in diverse and redundant, such that loss of some clones does not Downloaded from older humans. Clonal expansions originating in the naive generate holes in the repertoire; and 3) peripheral T cell ho- CD8 T cell compartment largely maintain a naive phenotype meostasis must be nonselective. The first two factors are highly and only a small fraction of these clones express memory cell interdependent and are influenced by the size of the species; markers. Moreover, TCR diversity in CD8 memory T cells is conditions for mice and humans are therefore very different. ∼10-fold lower than that of CD4 memory T cells, which Initial clonal size depends on intrathymic proliferation after would not be expected if a larger fraction of CD8 than CD4 TCR rearrangement, as well as the peripheral proliferation http://www.jimmunol.org/ naive T cells is converted into T cells with a memory phe- within the compartment that is at least partially empty, that is, notype (36). in the fetus as well as during the subsequent growth period up Alternatively, increased proliferation may be associated with to early adulthood. Data on increased naive T cell proliferation increased cell death, causing depletion of naive CD8 T cells. In in newborns support the notion that recent thymic emigrants modeling naive T cell division and survival, Reynolds et al. proliferate in the periphery to establish a minimal clonal size. (39) proposed that increased IL-7–driven proliferation, pos- More than 10% of cord T cells of infants born pre- sibly due to a lower threshold for IL-7 receptor signaling, maturely in the third trimester, when the human thymus starts leads to abrupt declines in compartment size several years to be active, are in the cell cycle (42). By fetal maturity this by guest on September 26, 2021 later. Taking this thought one step further, tonic TCR and frequency has declined, but it is still much higher than in homeostatic cytokine stimulation need to be optimally tuned young adults. Data on naive T cell turnover in children are to find the balance between providing sufficient signals for not available, but clonal expansion of thymic emigrants may survival and replacement without triggering increased turn- reach clonal sizes of 100 cells, a number that is consistent with over (38). Excess cytokines, such as those produced in in- TREC measurements in CD31+ T cells that presumably have flammatory conditions, increased expression of cytokine proliferated little or not at all after the initial seeding from the receptors such as CD25, or lowering of TCR and cytokine thymus (33). To determine how age affects TCR diversity in receptor thresholds may be detrimental for homeostasis and the adult, we performed an in silico simulation based on accelerate immune aging, similar to stem cells where cellular current estimates of kinetic parameters and clonal sizes (43). quiescence is important for delaying stem cell exhaustion and Even under the extreme scenario that thymic production stops aging (9, 40). Accordingly, accelerated aging has been de- at age 20 y and compartment size shrinks, we found that scribed in several autoimmune diseases (7, 8). diversity is only mildly reduced over lifetime, as long as ho- Obviously, these data are based on measurements of PBLs, meostatic proliferation is not highly selective. which represent ,3% of the total T cells in the body. A recent Recent progress in next-generation sequencing has allowed study by Thome et al. (41) quantified the T cell subset testing of these predictions and estimating the overall richness composition at nine anatomic tissue sites in 56 individual of the naive TCR repertoire. Initial estimates hovered around organ donors over a wide age range. Naive T cells were only a few million different TCRb-chains, an estimate of the same found in blood and lymphoid tissue. The distribution vari- magnitude as in the mouse, but much lower than those de- ance of naive CD4 and CD8 T cells between circulation and rived from concentrations of TRECs (44–46). The major lymphoid tissue was low. The impact of age on naive CD8 challenge of these sequencing studies continues to be ex- T cell decline was similar in blood and tissue, whereas the trapolating from the small analyzed sample to the entire blood frequencies of naive CD4 T cells may underestimate an compartment of close to 1012 T cells while not excluding age-associated decline in the lymphoid tissue. However, these infrequent sequences as possible PCR or sequencing errors. tissue data show relative frequencies and may therefore reflect Using a nonparametric analysis and multiple sampling, we increased frequencies of T effector memory cells, in particular arrived at a much higher richness estimate of close to 100 because CMV+ donors were not excluded. In conclusion, million different naive TCRb-chain sequences in young homeostatic proliferation appears to be sufficient for main- adults, suggesting that the human TCR repertoire is extremely taining a sizable naive CD4 T cell compartment whereas the diverse and it would require a massive contraction with age naive CD8 compartment declines in size, possibly as a con- to be functionally relevant (36). However, we only found 4076 BRIEF REVIEWS: AGE AND ADAPTIVE IMMUNITY a modest 2- to 5-fold contraction in repertoire richness for mere shortening is a consequence of homeostatic turnover. It both the naive CD4 and CD8 compartments when we ana- is intuitive to postulate that telomere attrition at least in part lyzed replicate samples of highly purified naive T cells from accounts for defective T cell responses in older individuals lymphopheresis samples of 70- to 85-y-old individuals. Al- (51). The ability to exhibit a proliferative burst with .10 cell though these individuals are certainly above average in their divisions within a short time frame is an absolute requirement health status, these data document that peripheral homeo- for an effective naive T cell response, and telomeric erosion static mechanisms are able to sustain a diverse repertoire. will curtail this burst. Keeping turnover low as long as it is Based on these studies we predict that thymic involution does sufficient to replace cell loss is therefore desirable and a pre- not have a detrimental influence on TCR diversity with age requisite of healthy aging, with the additional benefit of (Fig. 1). Differences in study design may explain why our avoiding clonality as discussed above. However, a replicative conclusion contradicts several earlier and also more recent history does not appear to be the only or major cause for studies that found a larger degree in diversity decline with age. telomere attrition. In early studies by Weng et al. (52), age- Most of the studies that describe a major contraction in the associated telomere attrition in naive T cells paralleled that of repertoire based their analyses on total T cell population in- memory T cells, although the kinetics of these two pop- stead of purified naive and subsets. The ob- ulations are vastly different. Moreover, telomere length did 2 served repertoire contraction could therefore only reflect not differ between CD31+ and proliferated CD31 naive a lower proportion of naive cells in the sample (46). More- T cells. In addition to being sensitive to replication, telomeres over, richness in older individuals is often underestimated are also subject to DNA damage, even more so than genomic Downloaded from because clonal sizes become increasingly non-Gaussian–dis- DNA. Because DNA repair mechanisms at telomeres are lim- tributed with clonally expanded T cells occurring even within ited by shelterin (a telomere-specific protein complex) (53), the naive repertoire. The increased clonality may result in DNA damage tends to persist and could be responsible for age- a low estimate of richness when the repertoire is not analyzed associated telomere attrition irrespective of proliferation. in sufficient depth. Estimates from studies, in particular, from the era prior to next-generation sequencing, therefore reflect Age and DNA damage in naive T cells http://www.jimmunol.org/ the increased clonality while not allowing conclusions on Accumulation of genetic damage in general is a characteristic richness (28). hallmark of aging in various tissues and settings (Table I) (9, Increased clonality is frequent with higher age, in particular, 54, 55). Its relevance is highlighted by the finding that many in the naive CD8 compartment (Fig. 1); some naive T cell premature aging syndromes are caused by underlying defects clones can reach a size usually only seen for memory T clones in DNA repair pathways (56). DNA damage responses in (36). Clonal selection may occur due to higher avidity to self- naive CD4 T cells have not been widely studied in the context , which in fact has been shown in animal studies (47), of aging, with the exception of the accelerated immune aging

or increased responsiveness to cytokines, which we have in patients with rheumatoid arthritis that has been linked to by guest on September 26, 2021 shown in simulation experiments, but which has not been defects in telomerase induction after activation and defects in studied in vivo. The increasing unevenness in clonal sizes in the MRN–ATM DNA repair pathway, both of which ren- older individuals is likely to bias the repertoire of T cells dered naive CD4 T cells susceptible to apoptosis (57–60). responding to a new antigenic challenge; more frequent T cell There is evidence that the defects identified in patients with clones will outcompete less frequent specificities. In principle, rheumatoid arthritis are also relevant for physiological aging. such a mechanism would be similar to what has been described DNA damage, as quantified by comet assay, gradually as “original antigenic sin” where T cell responses are biased increases with advancing age in memory T cells from healthy toward previous encounters of related Ags, although in this case controls. In comparison, DNA damage remains low in naive the bias would derive from uneven homeostatic proliferation, CD4 T cells up to 65 y, and increased DNA damage com- presumably due to self-recognition (48). One possible com- parable to memory T cells is only found in some individuals plication from excessive clonal expansion is a collapse of the in their seventh decade of life. The consequences of damage to repertoire diversity as predicted by in silico simulation (43). mitochondrial DNA (mtDNA), also a hallmark of aging, have Moreover, owing to the increased fitness of peripherally se- been explored even less for T cell aging (61, 62). mtDNA is lected clonotypes, ongoing thymic activity or thymic rejuve- particularly sensitive to cumulative DNA damage for a num- nation would not be efficacious to prevent or restore such ber of reasons. It is exposed to reactive oxygen species, whose a scenario because new thymic emigrants will not be able to major producer is the mitochondrion; it lacks protective compete (49). We predict that healthy immune aging will re- histones; and its repair mechanisms are less efficacious. quire prevention of increasing clonality. Because clonality is variable, valuable information should be learned from under- Metabolic pathways in T cells—tailored to T cell needs standing why clonality occurs more in some older individuals Taking a wider view, telomeric erosion, mitochondrial dys- than in others. function, in part caused by mtDNA damage, and DNA damage responses are closely intertwined with cell metabolism Age and telomere attrition in naive T cells (63, 64). Deregulated nutrient sensing is associated with or- Attrition of telomeres is an accepted hallmark of aging and is ganismal aging in many model systems (65). The insulin/ generally attributed to replicative history (Table I). Similar to insulin-like growth factor (IGF)-1 signaling pathway has stem cells, naive T cells are able to express telomerase, but been noted as a major aging-controlling pathway that is active their telomeres shorten with age (50). The current interpre- in various species throughout evolution (9). In contrast, reg- tation is that stimuli triggering homeostatic proliferation are ulation of metabolic pathways in T cells is less dependent on not sufficient to induce telomerase expression, and that telo- availability of insulin or IGF-1, but integral to T cell func- The Journal of Immunology 4077 tion, complicating the application of metabolic concepts in of this review, the evidence that increased constitutive ex- general aging to immune aging (Table I). The decisions of pression of p16 in T cells with age includes naive T cells is whether aerobic glycolysis or oxidative phosphorylation pre- only indirect and inconclusive (78). Older individuals may dominates and which fuel is being used are strictly linked to accumulate effector T cells, in particular in the setting of T cell activation and differentiation (66, 67). Similar to tu- chronic latent such as CMV. These cells are, by mor cells, aerobic glycolysis provides the building blocks en- nature of their differentiation state, less prone to proliferation abling proliferation and T cell expansion, an essential element but are otherwise fully functional (80, 81). T cell exhaustion, in particular for the naive T cell response. Metabolic pathways as found with chronic, actively replicating viral infections, is are closely intertwined with signaling events after TCR characterized by the expression of cell surface molecules such stimulation; for example, reactive oxygen species produced as as PD1 and TIM3 on memory and effector cell populations a result of mitochondrial activity play a key role in TCR- and very different from cellular senescence (82). induced signaling cascades. Moreover, many signaling mole- cules involved in T cell activation are also involved in the Functional alterations in naive T cells—a consequence of being no regulation of metabolic activity. Equally important, auto- longer completely naive? phagy is a key mechanism controlling T cell differentiation Naive T cells have a unique feature that is not appreciated as and survival (68, 69). Because the metabolic pathways and a general aging hallmark for all tissues, but which they share their relationship to signaling pathways in basic T cell biology with stem cells (Table I). To stay truly naive (or to remain are increasingly understood, it can be expected that these a fully pluripotent stem cell), naive T cells as well as stem cells Downloaded from insights will be fertile ground for immune aging studies. need to avoid differentiation. Stem cells develop an altered However, the scope of such studies will likely be different lineage potential with age: children and young adults have from the nutrition sensing studies in general aging research a dominant lymphoid lineage commitment in contrast to that try to curtail metabolic activity to prolong longevity, as older individuals who are biased toward myeloid differentia- exemplified with calorie restriction. Although data on naive tion. Changes in lineage commitment and partial differenti- T cells are lacking, initial studies have proven the value of ation in stem cells are related to DNA damage responses and http://www.jimmunol.org/ understanding metabolic pathways to explain defects in T the expression of the transcription factor BATF (83). Simi- memory cell function (70). In elderly CD4 memory T cells, larly, naive T cells can differentiate without having encoun- the increased expression of dual specific phosphatase 4 that tered exogenous Ag (37). Su et al. (84) described that healthy terminates nuclear ERK signaling and impairs proliferation individuals carry memory T cells to Ags they have never en- and effector functions is the result of increased activation of countered in life. These cells may be an example of cross- the metabolic master regulator AMP-activated protein kinase reactivity rather than the result of nonspecific differentiation (71). In the case of CD8 effector T cells that lack the ex- of naive T cells. However, virtual memory CD8 T cells have pression of CD28, but regain CD45RA and that have features been repeatedly identified in mice (85, 86). What drives the by guest on September 26, 2021 of cellular senescence, inhibition of p38 signaling induced clonal expansion of these cells in addition to recognition of autophagy and restored energy-dependent functions (72). self- is not known, nor is it clear if they are also present Finally, at least shown for murine T cells, T cell aging is as- in CD4 T cell populations or even at all in humans. TCR sociated with a defect in chaperone-mediated autophagy (69). sequencing studies have shown that clonal expansion occurs in the human naive T cell compartment, and more so for CD8 Cellular senescence—does it play a role in naive T cells? than for CD4 T cells (36). Most such clonally expanded cells Cellular senescence is a classical aging hallmark (Table I). In keep a naive phenotype, with expression of CD45RA, CD28, addition to stable cell cycle arrest, senescent cells show char- CD27, and CCR7; however, a small fraction of some clones acteristic phenotypic and functional changes, including the also expresses typical memory markers. On a broader scale, production of inflammatory cytokines (73). Although senes- expression of CD25 on naive CD4 T cells and CD95 on cence was originally attributed to telomeric erosion, non– a subset of naive CD8 T cells with age indicates partial ac- telomeric DNA damage can also trigger it by derepressing the tivation and/or differentiation (26, 31). Transcriptional and, INK4/ARF locus. The INK4A/ARF locus comprises over- even more so, epigenetic profiling could address whether lapping reading frames of two genes, p16INK4a and p19ARF, naive T cells have begun to differentiate with age and have that play important roles as cell cycle inhibitors in regulating transcriptional signatures reminiscent of memory genes or an cell growth and senescence and are mutated in various forms epigenetic landscape in which T effector genes are poised. of cancer (74, 75). In contrast to other forms of cellular se- Surprisingly, conclusive gene expression studies examining the nescence, p16-induced senescence is not associated with an impact of age on naive T cells in humans are missing; most of inflammatory phenotype (76). Derepression of INK4/ARF the array studies have either analyzed total CD4 and CD8 and transcription of p16 are seen with age in a variety of T cells or focused on memory T cells, where phenotypic tissues (77). T cells are no exception to this rule and even changes of CD28 loss and expression of NK cell surface show higher expression of p16 than do most other cells (78). markers with age have sparked particular interest (87). The However, p16 expression is also induced after T cell activation same is true for epigenetic studies. Alterations in DNA me- and appears to be a physiological mechanism to curtail clonal thylation patterns have been described with age, but only for expansion, particularly in an immune response of naive T cells unfractionated CD4 T cells (88). It remains to be determined (79). Whether naive T cells develop features of senescence in whether they reflect T cell differentiation or age-associated the classical sense is undetermined. As discussed above, there changes in naive and/or memory T cells. is no evidence that T cell turnover decreases with age; if Supporting evidence for the partial differentiation hy- anything, it increases in the very old. Important for the topic pothesis comes from identification of signaling alterations in 4078 BRIEF REVIEWS: AGE AND ADAPTIVE IMMUNITY older T cells (89). Reduced miR-181a expression is at least in of clonal expansion in naive T cells and differentiation into part the cause for subdued TCR signaling in naive cells with memory T cells involves pathways also concerned with cel- age. miR-181a controls the expression of DUSP6 and possi- lular senescence and DNA damage responses. Preliminary bly other phosphatases. Loss of miR-181a with age therefore evidence suggests that symmetries between T cell aging and increases DUSP6 activity, which in turn curtails ERK phos- differentiation also exist for regulatory programs controlled by phorylation after TCR stimulation (90). Interestingly, miR- miRNA expression. How far this concept can be expanded to 181a expression is regulated along a developmental pathway, include other aging hallmarks, in particular in the recently being highest in and lowest in memory and ef- emerged fields of T cell metabolism and autophagy, remains fector T cells (91). Because TCR signaling in memory T cells to be seen. Interventions to keep naive T cells quiescent would relies less on the LAT–ERK pathway and more on the hDlg– therefore be equally beneficial to prevent functional decline as p38 pathway (92), the lower concentration of miR-181a is well as repertoire distortion due to clonal expansions. not so important for memory cell activation, but it is detri- mental for aged naive T cells. 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