Thymic output and functionality of the IL‐7/IL‐7 receptor system in centenarians: implications for the neolymphogenesis at the limit of human life

Nasi, Milena; Troiano, Leonarda; Lugli, Enrico; Pinti, Marcello; Ferraresi, Roberta; Monterastelli, Elena; Mussi, Chiara; Salvioli, Gianfranco; Franceschi, Claudio; Cossarizza, Andrea

doi:10.1111/j.1474-9726.2006.00204.x

Cited by 111 publications

(97 citation statements)

References 58 publications

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“…The intrathymic supplementation of IL-7 in mice also failed to increase RTE during aging (40). Furthermore, a recent study in 44 centenarians noted the presence of TREC-bearing cells in the periphery, but no difference in IL-7 or IL-7 receptor-α mRNA could be detected in elderly compared with young and middle-aged individuals, suggesting a limited role for IL-7 alone in strategies for thymic renewal in aging (44). A number of studies have shown that activation of somatotropic axis and ablation of gonadal steroids promote thymic rejuvenation (24)(25)(26)(27)30), clearly suggesting the resilient nature of the thymus and its capacity for renewal.…”

Section: Figurementioning

confidence: 99%

Ghrelin promotes thymopoiesis during aging

Dixit¹,

Yang²,

Sun³

et al. 2007

J. Clin. Invest.

183

220

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The decline in adaptive immunity, T lymphocyte output, and the contraction of the TCR repertoire with age is largely attributable to thymic involution. The loss of thymic function with age may be due to diminished numbers of progenitors and the loss of critical cytokines and hormones from the thymic microenvironment. We have previously demonstrated that the orexigenic hormone ghrelin is expressed by immune cells and regulates T cell activation and inflammation. Here we report that ghrelin and ghrelin receptor expression within the thymus diminished with progressive aging. Infusion of ghrelin into 14-month-old mice significantly improved the age-associated changes in thymic architecture and thymocyte numbers, increasing recent thymic emigrants and improving TCR diversity of peripheral T cell subsets. Ghrelin-induced thymopoiesis during aging was associated with enhanced early thymocyte progenitors and bone marrow-derived Lin -Sca1 + cKit + cells, while ghrelin-and growth hormone secretagogue receptor-deficient (GHS-R-deficient) mice displayed enhanced age-associated thymic involution. Leptin also enhanced thymopoiesis in aged but not young mice. Our findings demonstrate what we believe to be a novel role for ghrelin and its receptor in thymic biology and suggest a possible therapeutic benefit of harnessing this pathway in the reconstitution of thymic function in immunocompromised subjects. IntroductionThe thymus is critical for the development, selection, and maintenance of the peripheral T cell pool possessing a broad spectrum of TCR specificities. The mammalian thymus is capable of generating T cells throughout the life span. However, after puberty and with advancing age, the thymic space becomes progressively filled with adipocytes coupled with a dramatic loss of thymocytes in the cortical and medullary areas, leading to a reduction in output of naive T cells. This process is called as thymic involution (1).The lack of a thymus in humans (DiGeorge syndrome) and thymectomy of neonatal mice lead to severe immunodeficiency due to paucity of mature T cells. During physiological aging, the total peripheral T cell pool is maintained by homeostatic expansion of preexisting T cells rather than replenishment by thymic export (2). Consequently, the long-lived naive T cell repertoire is reduced with an expansion of memory phenotype T cells, thereby limiting a host's ability to mount responses against new antigenic challenges. It has been demonstrated that defects in naive CD4 + T cells are also due to the chronologic age of the naive cells themselves rather than the chronologic age of the host (3). Involution of the thymus with age and lack or paucity of newly formed naive CD4 + T cells is therefore believed to be responsible for much of the deterioration in adaptive immunity and the resultant immune dysfunction in the elderly (4). However, several recent studies have demonstrated that the old thymus still retains the capacity for T cell lymphopoiesis with the ability to mount functional immune responses, albeit to a lim...

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Section: Figurementioning

confidence: 99%

Ghrelin promotes thymopoiesis during aging

Dixit¹,

Yang²,

Sun³

et al. 2007

J. Clin. Invest.

183

220

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“…The phenotypic features of centenarians, as far as the percentages of na€ ıve (CD45RA1, CCR71, defined T N ), central memory (CD45RA2, CCR71, defined T CM ), effector memory (CD45RA2, CCR72, defined T EM ), and terminally differentiated (CD45RA1, CCR72, defined T EMRA ) T cells are concerned, have been previously described in details (13). The donors included in this study had almost identical T cell differentiation patterns of those above quoted (13).…”

Section: Strategy For the Identification Of The Subpopulations Presenmentioning

confidence: 99%

“…The donors included in this study had almost identical T cell differentiation patterns of those above quoted (13). Data regarding the fine identification of the T cell populations were processed as shown in Figure 1.…”

Section: Strategy For the Identification Of The Subpopulations Presenmentioning

confidence: 99%

Subject classification obtained by cluster analysis and principal component analysis applied to flow cytometric data

et al. 2007

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Background: Polychromatic flow cytometry (PFC) allows the simultaneous determination of multiple antigens in the same cell, resulting in the generation of a high number of subsets. As a consequence, data analysis is the main difficulty with this technology. Here we show the use of cluster analysis (CA) and principal component analyses (PCA) to simplify multicolor data visualization and to allow subjects' classification. Methods: By eight-colour cytofluorimetric analysis, we investigated the T cell compartment in donors of different age (young, middle-aged, and centenarians). T cell subsets were identified by combining positive and negative expression of antigens. The resulting data set was organized into a matrix and subjected to CA and PCA. Results: CA clustered people of different ages on the basis of cytofluorimetric profile. PCA of the cellular subsets identified centenarians within a different cluster from

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“…Particularly, phenotypic analysis confirmed that the exhaustion of thymic output with age is at the basis of the deficient replacing of naïve T cells lost in the periphery and results in the inability to maintain the breadth of the T cell repertoire. Recently, the presence of TCR rearrangement excision circles (TREC+) cells in very few naïve T lymphocytes in centenarians has been demonstrated, suggesting that in such long-living subjects, these cells could either derive from residues of thymic lymphopoietic islets or even represent long-living lymphocytes that have not yet encountered their antigen [8] . Indeed, data in humans suggest that the replacement of thymic parenchyma with adipose tissue is a discontinuous process, reaching a maximum at around 50 years of age and not progressing further thereafter [9] .…”

Section: Changes In Adaptive Immunitymentioning

confidence: 99%

Immunosenescence and Immunogenetics of Human Longevity

Ostan

Bucci²,

Capri³

et al. 2008

Neuroimmunomodulation

163

100

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At present, individuals can live up to 80–120 years, a time much longer than that of our ancestors, as a consequence of the improvements in life conditions and medical care. Thus, the human immune system has to cope with a lifelong and evolutionarily unpredicted exposure to a variety of antigens, which are at the basis of profound age-related changes globally indicated as immunosenescence, a multifaceted phenomenon that increases morbidity and mortality due to infections and age-related pathologies. The major changes occurring during immunosenescence are the result of the accumulation of cellular, molecular defects and involutive phenomena (such as thymic involution) occurring concomitantly to a hyperstimulation of both innate and adaptive immunity (accumulation of expanded clones of memory and effector T cells, shrinkage of the T cell receptor repertoire, progressive activation of macrophages), and resulting in a low-grade, chronic state of inflammation defined as inflammaging. It is unknown whether inflammaging, which represents a risk factor for most age-related pathologies, is a cause or rather an effect of the aging process. In this complex scenario, the role of genetic background likely represents a fundamental variable to attain successful aging and longevity. Accordingly, centenarians seem to be equipped with gene variants that allow them to optimize the balance between pro- and anti-inflammatory molecules, and thus to minimize the effects of the lifelong exposure to environmental insults and stressors. The remarkable features of the genetics of aging and longevity are reviewed, stressing the unexpected and unusual results obtained regarding such a postreproductive type of genetics.

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Thymic output and functionality of the IL‐7/IL‐7 receptor system in centenarians: implications for the neolymphogenesis at the limit of human life

Cited by 111 publications

References 58 publications

Ghrelin promotes thymopoiesis during aging

Ghrelin promotes thymopoiesis during aging

Subject classification obtained by cluster analysis and principal component analysis applied to flow cytometric data

Immunosenescence and Immunogenetics of Human Longevity

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