T cell receptor excision circle assessment of thymopoiesis in aging mice

Sempowski, Gregory D.; Gooding, Maria E.; Liao, Hua Xin; Le, Phong T.; Haynes, Barton F.

doi:10.1016/s0161-5890(01)00122-5

Cited by 185 publications

(187 citation statements)

References 29 publications

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“…Studies have shown that thymic output in young rodents is substantial (26,27), and TREC dynamics, BrdU labeling, and thymic engraftment have demonstrated that the RTE pool in mice has a fast turnover (9,10,12,15). In line with previous studies, we found that thymectomy in young mice gives a considerable reduction in peripheral naïve T cell numbers already within 3 weeks after thymectomy (34,35), indicating an important contribution of RTEs to the naïve T cell population in young mice.…”

Section: Discussionsupporting

confidence: 91%

“…It is generally accepted that young rodents have considerable thymic output (26,27). BrdU-labeling, TREC dynamics and thymic engraftment in mice have revealed that the RTE pool of mice has a fast turnover (10,15), with an average life span of only 3 weeks (9,12). We first investigated whether this rapidly turning over RTE pool can be detected in young male mice, using the 2 H 2 O-labeling technique, and compared euthymic and thymectomized mice to establish to what extent RTEs affect the labeling within the naïve T cell pool.…”

Section: Resultsmentioning

confidence: 99%

“…In humans, naïve T cell numbers, T cell receptor excision circles (TRECs), and expression of CD31 have been used to measure thymic output (7,13,14). Dion et al (4) observed rapid changes in the Sj/V␤ TREC ratio within 3 months after infection with HIV, which suggested the presence of a rapidly turning over RTE pool in human adults containing most of the TRECs in the periphery, similar to young rodents and chickens (15,16). However, because TRECs are long-lived, none of these approaches is specific for T cells that have recently emigrated from the thymus (1,2,5), and, therefore, they fail to quantify thymic output in humans.…”

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confidence: 99%

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Sparse production but preferential incorporation of recently produced naïve T cells in the human peripheral pool

Vrisekoop

Braber

Boer

et al. 2008

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

201

327

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In mice, recent thymic emigrants (RTEs) make up a large part of the naïve T cell pool and have been suggested to be a distinct short-lived pool. In humans, however, the life span and number of RTEs are unknown. Although 2 H2O labeling in young mice showed high thymic-dependent daily naïve T cell production, long term upand down-labeling with 2 H2O in human adults revealed a low daily production of naïve T cells. Using mathematical modeling, we estimated human naïve CD4 and CD8 T cell half-lives of 4.2 and 6.5 years, respectively, whereas memory CD4 and CD8 T cells had half-lives of 0.4 and 0.7 year. The estimated half-life of recently produced naïve T cells was much longer than these average half-lives. Thus, our data are incompatible with a substantial short-lived RTE population in human adults and suggest that the few naïve T cells that are newly produced are preferentially incorporated in the peripheral pool. recent thymic emigrants ͉ T cell half-lives ͉ T cell production T he role of the thymus in HIV infection is still poorly understood (1, 2). On the one hand, thymic failure has been suggested to play a crucial role in CD4 T cell loss during HIV infection (3), and rapid thymic rebound has been proposed to be responsible for T cell reconstitution during anti-viral treatment (4). However, it has been argued that thymic output in adults might be too low to have a large impact on CD4 T cell depletion (5). In general, these issues are addressed with estimates of thymic output, naïve and memory T cell production rates, and life spans that are simply extrapolated from observations in mice, monkeys, and lymphopenic or irradiated humans (6-11).Naïve T cells are generally thought to turnover relatively slowly, but it has been suggested that, in mice, a considerable part of the naïve T cell pool consists of RTEs with relatively rapid turnover (9, 10, 12). In humans, naïve T cell numbers, T cell receptor excision circles (TRECs), and expression of CD31 have been used to measure thymic output (7,13,14). Dion et al. (4) observed rapid changes in the Sj/V␤ TREC ratio within 3 months after infection with HIV, which suggested the presence of a rapidly turning over RTE pool in human adults containing most of the TRECs in the periphery, similar to young rodents and chickens (15, 16). However, because TRECs are long-lived, none of these approaches is specific for T cells that have recently emigrated from the thymus (1, 2, 5), and, therefore, they fail to quantify thymic output in humans.Peripheral T cell proliferation might also contribute to the maintenance of the naïve T cell pool in human adults; however, it is unclear which fraction of these cells remains in the naïve T cell pool (17). The contribution of RTEs and peripheral T cell proliferation to the maintenance of the naïve T cell pool can only be determined by studying the fate of newly produced T cells. In vivo labeling with stable isotopes in combination with appropriate mathematical analysis of these data provides a way to obtain T cell decay and production rates ...

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Sparse production but preferential incorporation of recently produced naïve T cells in the human peripheral pool

Vrisekoop

Braber

Boer

et al. 2008

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

201

327

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“…Jamieson et al (1999) reported that thymopoietic potential per cell, as measured by the quantification of T-cell receptor excision circles (TRECs), remains constant up to 56 years and those thymocytes recognize a broad range of antigens. The maintenance of the thymopoietic potential per cell was subsequently confirmed in both mice (Sempowski et al 2002) and humans (Sempowski et al 2000;Gruver et al 2007). Nevertheless, none of these works assessed a direct association between thymic function-related markers and peripheral naive subsets.…”

Section: Introductionmentioning

confidence: 89%

Thymopoiesis in elderly human is associated with systemic inflammatory status

Ferrando‐Martínez

Franco

Hernández

et al. 2009

AGE

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Immunosenescence studies of age-related immune system damage focused on clinical lymphopenic situations or androgenic blockade have revealed new insights about adult human immune reconstitution. However, as far as we know, the extent of lymphopoiesis in the thymus of elderly humans remains unclear. To this effect, we have analyzed 65 adult human thymuses (from 36 to 81 years; median age 68.6 years) obtained from patients who underwent cardiac surgery. Our results show a correlation between CD4 + CD8 + double-positive (DP) cells and both the age (inverse) and percentage (direct) of peripheral naive T cells, indicating that the thymus is still able to affect the peripheral lymphocyte pool even in the elderly. We also found significant correlation between the degree of thymopoiesis and the inflammation markers, as shown by the inverse correlations between DP and the percentage of neutrophils and IL-6 levels and the percentage of peripheral lymphocytes. Furthermore, in a multivariate linear regression the percentage of DP and IL-7 levels, but not age, were independently associated with the percentage of neutrophils. In conclusion, the thymus maintains, even in the elderly, an active thymopoiesis that rejuvenates the peripheral naive T-cell pool. Moreover, age-related thymopoietic decay is associated with the peripheral inflammation markers.

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“…6 Administration of IL-7 has several stimulatory effects on T-cell development, including increased thymopoiesis in mice, both in vitro and in vivo 7,8 and T cell-dependent function in humans. 9 IL-7 was shown to increase the number of peripheral CD4 þ and CD8 þ antigens in non-activated T cells, 10 and enhance the anti-viral or anti-tumor activity of cytotoxic T cells that were clonally expanded in vitro for adoptive T-cell therapy.…”

Section: Introductionmentioning

confidence: 99%