Age-related CD8 T Cell Clonal Expansions Constrict CD8 T Cell Repertoire and Have the Potential to Impair Immune Defense

Messaoudi, Ilhem; LeMaoult, Joël; Guevara-Patiño, José A.; Metzner, Beatrix; Nikolich‐Žugich, Janko

doi:10.1084/jem.20040437

Cited by 214 publications

(182 citation statements)

References 47 publications

(79 reference statements)

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“…For example, IL-7 is believed to be the main regulator of N T cell turnover, and its administration to monkeys has been shown to increase N T cell proliferation (28). Based on our recent findings (19,29,30), the reduction in naïve T cell representation and diversity resulting from a mechanism of this kind would have the potential to adversely affect the induction of protective immunity.…”

Section: Discussionmentioning

confidence: 99%

Dramatic increase in naïve T cell turnover is linked to loss of naïve T cells from old primates

Čičin‐Šain¹,

Messaoudi²,

Park

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The loss of naïve T cells is a hallmark of immune aging. Although thymic involution is a primary driver of this naïve T cell loss, less is known about the contribution of other mechanisms to the depletion of naïve T cells in aging primates. We examined the role of homeostatic cycling and proliferative expansion in different T cell subsets of aging rhesus macaques (RM). BrdU incorporation and the expression of the G1-M marker Ki-67 were elevated in peripheral naïve CD4 and even more markedly in the naïve CD8 T cells of old, but not young adult, RM. Proliferating naïve cells did not accumulate in old animals. Rather, the relative size of the naïve CD8 T cell compartment correlated inversely to its proliferation rate. Likewise, T cell receptor diversity decreased in individuals with elevated naïve CD8 T cell proliferation. This apparent contradiction was explained by a significant increase in turnover concomitant with the naïve pool loss. The turnover increased exponentially when the naïve CD8 T cell pool decreased below 4% of total blood CD8 cells. These results link the shrinking naïve T cell pool with a dramatic increase in homeostatic turnover, which has the potential to exacerbate the progressive exhaustion of the naïve pool and constrict the T cell repertoire. Thus, homeostatic T cell proliferation exhibits temporal antagonistic pleiotropy, being beneficial to T cell maintenance in adulthood but detrimental to the long-term T cell maintenance in aging individuals.aging ͉ CD8 ͉ homeostasis T he immune system undergoes dramatic age-related changes in both structure and function. Of these, the best investigated and the most pronounced are the changes affecting aging T cells. Age-related changes were seen in T cell subset representation and T cell diversity in humans (1-3) and experimental animals (4, 5) and have been associated with higher mortality in the aging humans (6, 7). Moreover, impaired T cell activation has been documented in senescent rodent and human T cells (8)(9)(10)(11). Although the molecular lesions in T cell activation have been thoroughly studied, the picture of the age-related dysregulation of T cell populations is still emerging.Optimal protection against new or evolving pathogens requires a reserve of naïve T cells. However, naïve T cell production is reduced in old age because of the involution of the thymus. The maintenance of the naïve T cell compartment is further challenged by the lifelong consumption of naïve cells that respond to acute and persistent infections and become memory T cells. With age, the balance between naïve and antigenselected memory cells changes in favor of the latter, reducing the diversity of T cell receptors (TCRs). In fact, the aging naïve T cell population is reduced in both relative and absolute terms, suggesting that homeostatic mechanisms that maintain the size and the clonal diversity of the T cell repertoire progressively break down (12)(13)(14).T cells can also be replenished by extrathymic mechanisms, which rely on homeostatic proliferation in the absenc...

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Section: Discussionmentioning

confidence: 99%

Dramatic increase in naïve T cell turnover is linked to loss of naïve T cells from old primates

Čičin‐Šain¹,

Messaoudi²,

Park

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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123

124

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“…First, in humans, there are correlative data indicating that individuals with clonal expansions are less likely to respond successfully to an influenza vaccination (Saurwein-Teissl et al, 2002). Second, in mice, there are data that the presence of CD8 clonal expansions may result in very narrow holes in the T cell repertoire, which in some circumstances may impair immune responses to pathogens (Messaoudi et al, 2004). While these data indicate that clonal expansions may contribute to age-dependent immune compromise, it is important to note that affected individuals are not generally immune-suppressed.…”

Section: Impact Of Cd8 Clonal Expansions On Immune Function and Healthmentioning

confidence: 99%

“…clonality & increased competitive advantage relative to their neighbors), CD8 clonal expansions are clearly not tumors. First, individuals with expansions have no change in the total number of CD8 T cells (Messaoudi et al, 2004). Second, individuals (both humans and mice) live healthy lives with clonal expansions (Chamberlain et al, 2000), and the incidence of CD8 memory T cell tumors in humans is exceedingly rare.…”

Section: Impact Of Cd8 Clonal Expansions On Immune Function and Healthmentioning

confidence: 99%

CD8 T cell clonal expansions & aging: A heterogeneous phenomenon with a common outcome

Clambey

Kappler

Marrack

2007

Experimental Gerontology

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A highly diverse CD8 T cell repertoire is thought to be critical for maintaining appropriate immune defenses against a variety of pathogens. However, in many aged individuals, the diversity of T cell receptors is significantly reduced by the presence of large, monoclonal expansions of CD8 memory T cells. While ongoing research is focused on understanding the molecular alterations in these expansions, one major hurdle to this goal is the apparent heterogeneity of CD8 clonal expansions, which is apparent even in reductionist systems. In this review, we discuss current evidence that CD8 clonal expansions are a heterogeneous phenomenon, and our evolving understanding of what this heterogeneity tells us about CD8 memory T cell homeostasis and how it is altered in aged individuals. The phenomenon of CD8 clonal expansionsIn healthy, young individuals, the repertoire of antigen receptors (T cell receptors, TCRs) on CD8 T cells is highly diverse, with no single TCR dominating the repertoire. With increasing age, however, one common change to the TCR repertoire is the development of CD8 T cell expansions, in which a single clone of CD8 T cells, bearing a single TCR, occupies a significant proportion of the total CD8 T cell pool.CD8 T cell clonal expansions are a common age-dependent alteration, affecting about onethird of humans over the age of 65, and almost 60% of mice over the age of 2 years (Ku et al., 1997;Ricalton et al., 1998). While this phenomenon is common, the magnitude of CD8 clonal expansions can vary widely. In the most dramatic cases found in inbred mice, a CD8 clonal expansion (i.e. a single CD8 T cell specificity) can occupy 90% of the CD8 T cell repertoire (unpublished data), whereas in humans, CD8 clonal expansions can occupy up to 50% of the CD8 T cell repertoire.

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“…For example, aged humans with TCEs are less likely to respond successfully to influenza vaccination (7). Moreover, studies in mice indicate that the presence of TCEs may result in narrow holes in the T cell repertoire that, in some cases, may result in poor responses to pathogens that elicit a highly focused T cell response (6). TCEs are not tumors and do not appear to progress to malignancy over at least nine years (8).…”

mentioning

confidence: 99%

“…TCEs vary in size but can occupy a large portion of the total CD8 T cell pool (up to 50% in humans, up to 90% in mice) (unpublished data) (5). Individuals with TCEs have no change in the total number of CD8 T cells (6).…”

mentioning

confidence: 99%

Identification of two major types of age-associated CD8 clonal expansions with highly divergent properties

Clambey

White²,

Kappler³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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CD8 memory T cells are tightly regulated in young, healthy individuals but are often perturbed in aged animals by the appearance of large CD8 T cell clones. These clones are associated with impaired immunity in the aged. The molecular basis of this phenomenon remains unclear. Here, it is shown that the issue is confused by the fact that the clones are heterogeneous. Some clones bear high, and others, low levels of integrin ␣4 (itg␣4). These subtypes differ by multiple criteria. They appear in mice of different ages, concentrate in different tissues, and have different stabilities in vivo and responses to stimulation in vitro. itg␣4 high , but not itg␣4 low , CD8 clonal expansions have several characteristics consistent with a chronically stimulated phenotype. These properties include lowered levels of CD8, decreased expression of some cytokine receptors, and elevated expression of various inhibitory receptors, including the programmed death-1 (PD1) receptor and the killer cell lectin-like receptor G1 (KLRG1). The characteristics of itg␣4 high clonal expansions suggest that they may arise from age-dependent alterations in antigen expression and tolerance. These data redefine CD8 clonal expansions into at least two distinct entities and indicate that there are multiple mechanisms that drive age-related alterations of CD8 T cell homeostasis.aging ͉ CD8 T cell ͉ homeostasis ͉ T cell memory

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Age-related CD8 T Cell Clonal Expansions Constrict CD8 T Cell Repertoire and Have the Potential to Impair Immune Defense

Cited by 214 publications

References 47 publications

Dramatic increase in naïve T cell turnover is linked to loss of naïve T cells from old primates

Dramatic increase in naïve T cell turnover is linked to loss of naïve T cells from old primates

CD8 T cell clonal expansions & aging: A heterogeneous phenomenon with a common outcome

Identification of two major types of age-associated CD8 clonal expansions with highly divergent properties

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