Thymic atrophy in the mouse is a soluble problem of the thymic environment
Introduction
An age-related increase in the susceptibility to certain infections, an increased incidence of autoimmune disease, and certain cancers [1], [2], [3] are the clinical manifestation of an immune system which is not functioning to its full capability. These traits, coupled with the laboratory investigations revealing a reduced ability of the T lymphocytes from old individuals, compared with younger individuals, to perform in functional assays in vitro indicate the decline in the efficient functioning of the immune system with age [4], [5].
One possibility is that this immune dysfunction may be due to a loss of lymphocytes from the peripheral T cell pool. However, experiments in both humans and mice suggest that there are no age-related changes in the total number of lymphocytes or in the number of CD4+ or CD8+ T lymphocytes within the peripheral lymphoid pool [6], [7], [8]. The inference from these results is that the immune dysfunction must be related to the properties of the T lymphocytes in the periphery. Since changes in these properties are age-related they must be consequent upon an age-related change in the production and maintenance of the peripheral T cell pool. Within this pool of cells, the αβTCR+ T lymphocytes constitute the major population and are produced mainly by the thymus. Studies in several species have shown that the rate at which the thymus produces these cells declines with age [9], [10], [11] indicating that reduced thymic output is linked to declining immune function.
One proposal is that the total number of cells in the peripheral T cell pool remains unchanged because memory T cells proliferate to compensate for the loss of thymic output. The naı̈ve T cell pool therefore diminishes with age, and the memory cell pool expands. The outcome of this homeostatic mechanism is the potential, as an individual grows older, to produce memory cells which through repeated rounds of proliferation are at or close to their replicative limit. Advancing age would then be associated with an increase in the number of T cells unable to proliferate to a stimulus which induces a proliferative response in the T cells from younger individuals, a common finding [12], [13], [14], [15]. If thymic atrophy could be prevented or reversed and thymic output maintained, then based on this proposal one should be able to prevent the onset of age-associated T cell immune dysfunction. In order to reverse or prevent thymic atrophy it is important to understand the process by which αβTCR+ T cells are produced in the thymus.
Section snippets
Stages in the production of an αβ T cell
The emergence of a naı̈ve αβTCR+ T cell from the thymus is the culmination of a number of differentiation processes which in adults originates with multipotential stem cells in the bone marrow. The earliest precursors of the T cell pathway in the adult thymus are CD3−CD4loCD8− [16]. This population has been subdivided on the basis of expression of CD44 and CD25, with the most immature stage identified as CD44+CD25−. Differentiation from this stage involves the transient expression of CD25 and
General considerations
Atrophy of the thymus has been described in many species. The thymus in humans weighs about 10–15 g at birth 30–40 g at puberty and 10–15 g at 60 years of age [24]. In male C57Bl/10 mice the thymus weighs about 50 mg at 3 months of age, reducing to approx. 20 mg by 20 months of age [25]. Thymic atrophy begins early in life in both man [26] and mouse [27] and there appear to be gender related differences with atrophy occurring at a faster rate in males than in females [28], [29], [30].
Analysis
Causes of thymic atrophy
There are several hypotheses to cover the causes of thymic atrophy, which have looked at several of the components which contribute towards the production of thymocytes. These are dealt with below.
IL-7 and thymic atrophy, a current hypothesis
The hypothesis that we currently hold is that age-associated thymic atrophy results from defects in the thymic microenvironment, which lead to a reduction in the amount of available IL-7.
Acknowledgements
We would like to thank Dr Nesrina Imami for fruitful discussions and for reading this manuscript. This work was supported by the Wellcome Trust (Grant No. 051541).
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2012, Seminars in ImmunologyCitation Excerpt :This in turn has stimulated studies in multiple laboratories aimed at defining the causes of age-related thymic involution and using this information to reverse that process. These efforts have identified multiple processes contributing to thymic involution that include altered production of various endocrine hormones [1,2], deterioration of the thymic microenvironment [3,4], and a reduction in the number and quality of T cell precursors [5–7]. While each may independently contribute to thymus involution, it is increasingly clear that changes in one parameter may in turn trigger changes in the others.