Elsevier

Vaccine

Volume 18, Issue 16, 25 February 2000, Pages 1629-1637
Vaccine

Thymic atrophy in the mouse is a soluble problem of the thymic environment

https://doi.org/10.1016/S0264-410X(99)00498-3Get rights and content

Abstract

Age related deterioration in the function of the immune system has been recognised in many species. The clinical presentations of such immune dysfunction are an age-related increased susceptibility to certain infections, and an increased incidence of autoimmune disease and certain cancers. Laboratory investigations reveal a reduced ability of the cells from older individuals, compared with younger individuals, to perform in functional in vitro assays. These manifestations are thought to be causally linked to an age associated involution of the thymus, which precedes the onset of immune dysfunction. Hypotheses to account for the age-related changes in the thymus include: (i) an age related decline in the supply of T cell progenitors from the bone marrow (ii) an intrinsic defect in the marrow progenitors, or (iii) problems with rearrangement of the TCR β chain because of a defect in the environment provided by the thymus. We have analysed these possible options in normal mice and also in mice carrying a transgenic T cell receptor. The results from these studies reveal no age related decline either in the number of function of T cell progenitors in the thymus, but changes in the thymic environment in terms of the cytokines produced. We have shown that specific cytokine replacement therapy leads to an increase in thymopoiesis in old animals.

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 CD3CD4loCD8 [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).

References (68)

  • Office of National Statistics,...
  • The Government Actuary’s Department,...
  • I.D Gardner

    The effect of aging on susceptibility to infection

    Rev. Infect. Dis.

    (1980)
  • K Flurkey et al.

    Cellular determinants of age-related decrements in the T-cell mitogen response of B6CBAF1 mice

    J. Gerontol.

    (1992)
  • E.T Bloom et al.

    Cellular and molecular mechanisms of the IL-12-induced increase in allospecific murine cytolytic T cell activity. Implications for the age-related decline in CTL

    J. Immunol.

    (1994)
  • Hannet I, Erkeller Yuksel F, Lydyard P, Deneys V, DeBruyere M. Developmental and maturational changes in human blood...
  • M Utsuyama et al.

    Age-related changes of splenic T cells in mice–a flow cytometric analysis

    Mech. Ageing. Dev.

    (987)
  • C.L Mackall et al.

    Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy [see comments]

    N. Engl. J. Med.

    (1995)
  • C.L Mackall et al.

    Thymic aging and T-cell regeneration

    Immunol. Rev.

    (1997)
  • J Kampinga et al.

    Post-thymic T-cell development in the rat

    Thymus

    (1997)
  • R Schwab et al.

    Immunological studies of ageing. X. Impaired T lymphocytes and normal monocyte response from elderly humans to the mitogenic antibodies OKT3 and Leu 4

    Immunology

    (1985)
  • T Zhou et al.

    Prevention of age-related T cell apoptosis defect in CD2-fas-transgenic mice [see comments]

    J. Exp. Med.

    (1995)
  • M.V Hobbs et al.

    Cell proliferation and cytokine production by CD4+ cells from old mice

    J. Cell Biochem.

    (1991)
  • D.M Murasko et al.

    Decline in mitogen induced proliferation of lymphocytes with increasing age Decline in mitogen induced proliferation of lymphocytes with increasing age

    Clin. Exp. Immunol.

    (1987)
  • L Wu et al.

    CD4 expressed on earliest T-lineage precursor cells in the adult murine thymus

    Nature

    (1991)
  • D.I Godfrey et al.

    A developmental pathway involving four phenotypically and functionally distinct subsets of CD3–CD4–CD8-triple-negative adult mouse thymocytes defined by CD44 and CD25 expression

    J. Immunol.

    (1993)
  • D.I Godfrey et al.

    Onset of TCR-beta gene rearrangement and role of TCR-beta expression during CD3–CD4–CD8- thymocyte differentiation

    J. Immunol.

    (1994)
  • S.C Jameson et al.

    Positive selection of thymocytes

    Annu. Rev. Immunol.

    (1995)
  • D Brandle et al.

    Engagement of the T-cell receptor during positive selection in the thymus down-regulates RAG-1 expression

    Proc. Natl. Acad. Sci. USA

    (1992)
  • H.T Petrie et al.

    Multiple rearrangements in T cell receptor alpha chain genes maximize the production of useful thymocytes

    J. Exp. Med.

    (1993)
  • S.M Alam et al.

    T-cell-receptor affinity and thymocyte positive selection [see comments]

    Nature

    (1996)
  • C Penit et al.

    Expansion of mature thymocyte subsets before emigration to the periphery

    J. Immunol.

    (1997)
  • M.D Kendall et al.

    The weight of the human thymus gland at necropsy

    J. Anat.

    (1980)
  • R Aspinall

    Age-associated thymic atrophy in the mouse is due to a deficiency affecting rearrangement of the TCR during intrathymic T cell development

    J. Immunol.

    (1997)
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