Changes in thymic function with age and during the treatment of HIV infection

Douek, Daniel C.; McFarland, Richard; Keiser, Phillip H.; Gage, Earl A.; Massey, Janice M.; Haynes, Barton F.; Polis, Michael A.; Haase, Ashley T.; Feinberg, Mark B.; Sullivan, John L.; Jamieson, Beth D.; Zack, Jerome A.; Picker, Louis J.; Koup, Richard A.

doi:10.1038/25374

Cited by 1,721 publications

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“…New tools have been recently developed to better assess thymus function. Using a molecular marker of recent thymic emigrants, a DNA circle from the T-cell rearrangement process named TREC [8], an increase in naïve T-cells carrying this circle after HAART has been described [9]. Another approximation to assess the thymus role in HIV-1 infected patients would be the evaluation of thymic volume by computed tomography (CT).…”

Section: Introductionmentioning

confidence: 99%

Changes in thymus volume in adult HIV-infected patients under HAART: correlation with the T-cell repopulation

Rubio

Martı́nez-Moya

Leal

et al. 2002

Clinical and Experimental Immunology

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SUMMARYAn important thymus role has been suggested in T-cell repopulation after HAART in adult HIV-1 infected patients. Thymus volume increase after treatment has been described in HIV-1 infected children but not in adult patients. The objective of this work was to evaluate the effect of HAART on the thymic volume of adult HIV-1 infected patients and its relation with the T-cell repopulation. Twenty-one adult patients following 24 weeks under HAART were included in the study. All patients underwent a thoracic computed tomography (CT) evaluation for the measurement of thymic volumes at weeks 0, 12 and 24.Baseline thymus volume showed a significant correlation with the patient's age. Thymic volume significantly increased after 24 weeks of HAART. Besides, a significant correlation between changes in the thymus volume and changes in both total and naïve CD4+ cell counts was found. Only patients with increases ≥ 100 CD4+ cell counts after treatment significantly increased the thymic volume.These data show the first evidence of an early change in thymic volume of adult HIV-1 infected patients under HAART. This increase was related to the rise of both total and naïve CD4+ cell counts suggesting a functional role of thymic volume increase.

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Section: Introductionmentioning

confidence: 99%

Changes in thymus volume in adult HIV-infected patients under HAART: correlation with the T-cell repopulation

Rubio

Martı́nez-Moya

Leal

et al. 2002

Clinical and Experimental Immunology

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“…Thymic epithelial space, which is the best biological correlate of functionally active tissues, declines from about 7 cm 3 in the young adult to about 1 cm 3 in the 55 to 65 year old. Recent studies have shown islands of functional tissue in the thymus of the elderly (Haynes et al, 2000;Steinmann et al, 1985;Steinmann, 1986); however, it is uncertain whether production of new thymocytes in these residual tissues is of quantitative importance.In the absence of phenotypic markers specific for thymic emigrants, most studies of thymic output have relied on measuring T-cell receptor excision circles (TREC) (Douek et al, 1998;Kong et al, 1999). These signal-joint TRECs are formed during T-cell receptor (TCR)-α-chain rearrangement, when a substantial portion of the TCR δ locus is excised.…”

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confidence: 99%

“…Even naïve T cells are, therefore, present in identical replicates generated during and shortly after T-cell development in the thymus or in the periphery. Estimates of clonal sizes have come from the dilution of TRECs during thymic development (Douek et al, 1998;Okamoto et al, 2002). We have used TREC measurements in cord blood of babies born at different gestational ages (Schonland et al, 2003).…”

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confidence: 99%

Aging and T-cell diversity☆

Goronzy

Lee

Weyand

2007

Experimental Gerontology

237

187

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Naïve and memory CD4 and CD8 T cells represent a highly dynamic system with constant homeostatic and antigen-driven proliferation, influx, and loss of T cells. Thymic activity dwindles with age and essentially ceases in the later decades of life, severely constraining the generation of new T cells. Homeostatic control mechanisms are very effective to maintain a large and diverse subset of naïve CD4 T cells for many years up to the 8 th decade of life, but eventually and abruptly fail at about the age of 75 years. In contrast, the CD8 T cell compartment is more unstable, with progressive diminution of naïve T cells and increasing loss of diversity already during mid adulthood. Vaccination strategies need to aim at developing a broad repertoire of memory T cells before the critical time period when the naïve CD4 T-cell repertoire collapses. Research efforts need to aim at understanding the homeostatic control mechanisms to ultimately expand the time period of repertoire stability.Adaptive immune responses are initiated when T cells recognize endogenous antigen on activated and mature antigen-presenting cells. Successful responses depend on the repertoire of existing T cells (Nikolich-Zugich et al., 2004). The diversity of the T-cell compartment determines whether T cells are available that recognize antigen with high avidity. The frequency of each T-cell specificity in the existing repertoire influences how fast an initial immune recognition event can be amplified to generate a sufficient number of effector cells. Consequently, the naïve T-cell repertoire is highly diverse, providing the ability to recognize the universe of exogenous and potentially dangerous antigens. In contrast, the memory T-cell repertoire is selected by previous antigen exposure. Each memory T cell clone is present in larger frequency, guaranteeing a more rapid response upon re-exposure to the same antigen. Homeostatic regulation is important not only to control the size of the T-cell compartment, but also the composition of naïve and memory T cells, as well as the diversity of each T-cell compartment (Goldrath and Bevan, 1999a). T cell homeostasis and ageThe homeostatic control mechanisms have to deal with exogenous and endogenous challenges (Freitas and Rocha, 2000;Jameson, 2002). The T-cell compartment is a highly dynamic T-cell reservoir with sometimes conflicting kinetics of singular components that compete for space. The most evident example is the clonal expansion that occurs after naïve or memory T cells encounter antigen. This clonal expansion is dramatic and has been estimated to include 10 to 15 population doublings followed by equally rapid clonal contraction with a majority of *Corresponding author. Mailing address: Lowance Center for Human Immunology, Emory University School of Medicine, 101 Woodruff Circle #1003, Atlanta, GA 30322. Phone: (404) 727-7310. Fax: (404) 727-7371. E-mail: E-mail: jgoronz@emory.edu.. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As...

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“…The reduction in the cell number of the thymic microenvironment over the years is a genetically pre-programmed and well-controlled physiological process, 22 and is reflected in the slow-down of T-cell export observed in normal individuals already in the first years of life. 23 Thus, it can be speculated that PRSS16 has a function in thymic development. The only splice variant of PRSS16 that was constitutively expressed in nearly all samples, independently of the age of the donor, is PRSS16-4.…”

Section: Discussionmentioning

confidence: 99%

Alternatively spliced transcripts of the thymus-specific protease PRSS16 are differentially expressed in human thymus

Luther

Wienhold

Oehlmann³

et al. 2004

Genes Immun

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The putative serine protease PRSS16 is abundantly expressed in the thymic cortex and the gene is encoded within the HLA I complex. Although its function is not yet defined, the very restricted expression points to a role in T-cell development in the thymus. In this study, we show that the PRSS16 mRNA is alternatively spliced to generate at least five transcripts. Apart from the full-length sequence, we found two other isoforms with all putative active site residues of the serine protease, suggesting that those variants may also be functional. Semi-quantitative analysis of the splice variants in different tissue samples revealed a strong correlation between the specific formation of alternatively spliced PRSS16 transcripts and the age and thymus pathology status of the donor. Newborn thymi express mostly the PRSS16-4 and -5 isoforms and lack the PRSS16-1 transcript, which appears around 2 years of age and stays until adulthood. Incidentally, thymi from myasthenia gravis (MG) patients with thymoma showed a marked decrease in the expression of the full-length PRSS16-1 and increased expression of the smaller isoforms. The data suggest a potential role of the PRSS16 isoforms in the postnatal morphogenesis of the thymus and in the thymus pathology related to MG.

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Changes in thymic function with age and during the treatment of HIV infection

Cited by 1,721 publications

References 27 publications

Changes in thymus volume in adult HIV-infected patients under HAART: correlation with the T-cell repopulation

Changes in thymus volume in adult HIV-infected patients under HAART: correlation with the T-cell repopulation

Aging and T-cell diversity☆

Alternatively spliced transcripts of the thymus-specific protease PRSS16 are differentially expressed in human thymus

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