Thymopoiesis in elderly human is associated with systemic inflammatory status

Ferrando‐Martínez, Sara; Franco, Jaime M.; Hernández, Ana; Ordoñez, Antonio; Gutiérrez, E.; Abad, A.; Leal, Manuel

doi:10.1007/s11357-008-9084-x

Cited by 58 publications

(44 citation statements)

References 39 publications

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“…1d). As previously showed (Ferrando-Martinez et al 2009) elderly individuals show a wide range of thymic functionality that directly affects the naive T cell pool. Percentages of DP thymocytes were analyzed as thymic function gold standard and a representative flow cytometry example is shown as Fig.…”

Section: Analysis Of Naive T Cells Homeostatic Parametersmentioning

confidence: 71%

“…The slight lymphopenia shown in elderly people reduces self-MHC contacts, needed for naive homeostasis (Takada and Jameson, 2009). Besides, IL-7 availability is maintained, or even increased (Ferrando-Martinez et al 2009). Since naive T cell compartment is independently regulated, less MHC contacts, and stronger IL-7-derived survival signals (described as sense of a naive immune space) allow naive T cells to proliferate in a similar way as naive T cells transferred to lymphopenic hosts do (Ernst et al 1999).…”

Section: Discussionmentioning

confidence: 99%

“…As previously confirmed, the aged thymus in these subjects remained clearly distinguishable despite the adipose tissue of the mediastinum. The existence of Hassall's Corpuscles even in tissues showing 0% DP guarantee the accuracy of thymus identification and representative sample taking (Ferrando-Martinez et al 2009 Cell sorting Cryopreserved PBMCs were stained using anti-CD45RA FITC, anti-CD4 PE, anti-CD27 PE-Cy5 and anti-CD8 PE-Cy7 monoclonal antibodies (Becton Dickinson, San Jose, CA). Naive CD8 ( Signal-joint T cell Receptor Excision Circle levels Signal-joint T cell Receptor Excision Circle (sj-TREC) numbers were analyzed in sorted naive T cells.…”

Section: Methodsmentioning

confidence: 99%

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Age-related deregulation of naive T cell homeostasis in elderly humans

Ferrando‐Martínez

Ruiz‐Mateos

Hernández

et al. 2010

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Immunosenescence is characterized by phenotypic and functional changes of effector memory T cells. In spite of the well-described senescent defects of these experienced T cells, immune responses to new pathogens are also deeply affected in elderly humans, suggesting that naive T cells could also show age-related defects. It has been reported in both, animal models and humans, alterations of the naive T cell turnover associated to advanced age or low thymic function. However, as far as we know, homeostatic mechanisms involved in the deregulation of naive T cell peripheral dynamics and their consequences are still not well understood. Thus, the aim of our study was to analyze homeostatic parameters of peripheral naive T cells and their relationship with thymic function in young and elderly humans. Our results show that lower naive T cell numbers were associated with a lower thymic function and higher activation and proliferating naive T cell levels. We then analyzed sjTREC numbers and relative telomere length from sorted naive T cells. Our results show that the aberrant activation and proliferation status was related to lower sjTREC numbers (a peripheral proliferation marker) and both, higher CD57 expression levels and shortened telomeres (replicative senescence-related markers). Elderly individuals show a greater contraction of the CD8 naive T cell numbers and all homeostatic alterations were more severe in this compartment. In addition, we found that low functional thymus show a CD4-biased thymocyte production. Taken together, our results suggest a homeostatic deregulation, affecting mostly the naive CD8 T cell subset, leading to the accumulation of age-associated defects in, otherwise, phenotypically naive T cells.

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Section: Analysis Of Naive T Cells Homeostatic Parametersmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Age-related deregulation of naive T cell homeostasis in elderly humans

Ferrando‐Martínez

Ruiz‐Mateos

Hernández

et al. 2010

AGE

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“…Our results show that thymic function-related deterioration of the adaptive response and systemic inflammation act independently by affecting human survival. Despite the well-described age-related atrophy (Chiodi 1940;Henry 1967), we have previously shown that thymic function in elderly humans is widely heterogenic, and the thymus that remains functional in elderly individuals has a direct role in the peripheral T cell pool maintenance (Ferrando-Martínez et al 2009). In addition, a higher elderly thymic function correlates with younger and better-preserved peripheral naive T cell subset (Ferrando-Martínez et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Thymic function failure and C-reactive protein levels are independent predictors of all-cause mortality in healthy elderly humans

Ferrando‐Martínez

Romero-Sánchez

Solana

et al. 2011

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Relationship between thymic function and elderly survival has been suspected, despite the fact that formal proof is elusive due to technical limitations of thymic function-related markers. The newly described sj/β-TREC ratio allows now, by overcoming these limitations, an accurate measurement of thymic output in elderly humans. Thus, the aim of this study was to determine the impact of thymic function and inflammatory markers on healthy elderly human survival. Healthy volunteers (n=151), aged over 65, were asked to participate (CARRERITAS cohort). Subjects were excluded if diagnosed of dementia or, during the last 6 months, had clinical data of infection, hospital admission, antitumor therapy, or any treatment that could influence the immune status. Thymic function (sj/β-TREC ratio), CD4:CD8 T cell ratio, C-reactive protein, interleukin-6, and neutrophilia were determined from basal samples. All basal variables and age were associated with 2-year allcause mortality. Multivariate analysis showed that only thymic function and C-reactive protein were independently associated with time to death. In conclusion, we show, for the first time, the direct role of thymic function in human survival. C-reactive protein raise is also a marker of mortality in the healthy elderly, in a thymic-independent way.

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“…Thymopoietic degree is widely heterogeneous among individuals (Figure 3). In addition, thymic function in elderly people has an active role in the peripheral immune system rejuvenation (Ferrando-Martínez et al, 2009). Higher thymic function in elderly human is associated with a better preservation of the immune system.…”

Section: Thymic Failure During Adulthood and Elderlymentioning

confidence: 99%