Trends in Molecular Medicine
Volume 8, Issue 10, 1 October 2002, Pages 469-476
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Review
Thymic regeneration: teaching an old immune system new tricks

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Abstract

Recent studies in mice and humans show that the importance of the thymus extends well beyond the initial seeding of the peripheral T-cell pool. Although peripheral homeostasis can maintain T-cell numbers, the thymus is the major, if not the exclusive, source of new T-cell specificities. With age, thymus atrophy dramatically reduces the export of new T cells and predisposes an individual to impaired T-cell function, reduced T-cell immunity, and increased autoimmunity. Thymus atrophy is also the primary obstacle to restoration of the T-cell pool in the aftermath of HIV treatment or lymphoablative therapies. Here, we review thymus T-cell production, with particular attention to the factors that influence thymocyte export, and examine the impact that recent thymic emigrants have on the peripheral pool. In the future, thymic regeneration might become a feasible and potentially powerful approach to rejuvenating a depleted peripheral T-cell pool.

Section snippets

Export from the thymus

After a differentiation process of about four weeks (in mice), mature thymocytes congregate near the lymphatics and blood vessels of the medulla and are exported at a remarkably consistent rate of 1–2% of total thymocytes per day [5]. The emigration process is not well defined, but recent thymic emigrants (RTE) display little of the phenotypic or functional immaturity evident among most medullary thymocytes, suggesting that functional maturity probably determines when export from the thymus

Incorporation of recent thymic emigrants by the peripheral pool

In mice, RTE begin to seed the peripheral T-cell pool late in embryogenesis and continue to be exported from the thymus at a rate of 1–2% of thymocytes per day throughout life [5]. Because the size of the peripheral T-cell pool is thought to be homeostatically regulated, there was doubt about whether RTE are incorporated when T-cell numbers are normal and therefore, according to homeostatic theory, at a maximum [18]. However, contrary to suggestions that T-cell numbers are maintained at a

Benefits of thymic export

RTE leave the thymus with their specificity for antigen determined by the productive rearrangement and expression of T-cell receptor genes. This random process occurs early in thymocyte development and the number of potential gene configurations far exceeds the number of T cells produced in a lifetime. Therefore, the accumulation of RTE provides for extraordinary receptor diversity and the pool is likely to contain T cells capable of recognizing and responding to virtually any pathogen the host

Homeostatic regulation of thymic export?

Given the impact of thymic export on the peripheral T-cell pool, it would be of great benefit if the active control of thymocyte export extended beyond a simple discrimination between mature and immature cells. For example, the size, composition and diversity of the peripheral T-cell compartment could theoretically be regulated by slowing thymic export when the periphery was ‘full’ and increasing it in times of lymphopenia [29]. A recent study described changed levels of T-cell receptor

RTE phenotype and detection

An evaluation of thymus function is particularly important for patients recuperating from lymphoablative treatments such as chemo- and radio-therapy, or from diseases that cause immunodepletion, such as HIV. Improved thymic function generally improves the rate, and long-term effectiveness, of T-cell reconstitution and immune recovery and, as a result, there is significant clinical value in establishing a reliable system to measure thymic export levels 24., 29.. Unfortunately, the task is

T-cell receptor gene excision circles

Recently, many clinicians and researchers have come to regard the concentration of TRECs in the blood as a reliable indicator of RTE levels, and have extrapolated estimates of the rate of thymic export from these data 36., 37.. TRECs are formed when developing thymocytes rearrange T-cell receptor genes, causing the excision of unused DNA fragments between the V, D and J elements [38]. The resulting TRECs are relatively stable, do not replicate during cell division, and are diluted between

The future: therapeutic reversal of thymus atrophy

Many immune problems associated with aging or lymphopenia could, in theory, be alleviated by increased thymic export. The plasticity of the T-cell pool makes it receptive to this form of intervention, but because the rate of thymic export (when measured as a proportion of thymus size) is not responsive to imbalances in the peripheral pool, the only means of producing a sustainable increase in export levels is to increase thymic mass (Fig. 4).

In mice, the transplantion of additional thymuses is

Acknowledgements

We acknowledge the ongoing support of the National Health and Medical Research Council of Australia. S.P.B is an awardee of a Human Frontiers Science Program Long Term Fellowship.

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