Trends in Immunology
ReviewImmune senescence special issue. Free access sponsored by the National Institutes of HealthThymic involution and immune reconstitution
Introduction
The thymus is a vital organ for homeostatic maintenance of the peripheral immune system. It is in this mediastinal tissue that T cells develop and are extensively educated for export to the periphery and establishment of a functional and effective immune system (Box 1). One of the striking paradoxical features of the thymus is that it undergoes profound age-associated atrophy. Loss of thymic epithelial space (TES), i.e. thymus involution or atrophy, results in less efficient T-cell development, or thymopoiesis, and decreased emigration of naïve T cells. Under most circumstances, thymic decline is of minimal consequence to a healthy individual, but the reduced efficacy of the immune system with age has direct etiological linkages with an increase in diseases including opportunistic infections, autoimmunity and the incidence of cancer (see articles by Chen et al. and Weksler et al. also in this issue). Furthermore the inability of adults to restore immune function after insult induced by chemotherapy, ionizing radiation exposure and infections (e.g. HIV-1) leads to increased morbidity and often mortality in the aged. For these reasons, it is important to understand what drives normal age-related thymic atrophy and loss of thymic output. Elucidation of these crucial mechanisms and systems will allow us to better prevent or treat immunosenescence-associated problems in an aging world.
Important advances have begun to shed light on the intricate processes that mediate chronic age-associated thymic involution. In this review, we will present the emerging paradigm that thymus tissue homeostasis is regulated by a balance of thymosuppressive and thymostimulatory factors and the potential for these pathways to be exploited for therapeutic thymus restoration and peripheral immune reconstitution.
Section snippets
Age-related thymic atrophy (human and mouse)
In 1985, Steinman defined the morphology of the human thymus and elegantly demonstrated that thymic function gradually starts to decrease from the first year of life [1]. Crucial to this observation was the appreciation of dual components of the human thymus, the true thymic epithelial space (TES) in which thymopoiesis occurs and the nonepithelial, nonthymopoietic perivascular space (PVS) [1]. The TES (cortex and medulla) contains keratin-positive thymic epithelium that nurtures developing
Enhancement of immune reconstitution by cytokine modulation
Cytotoxic therapies such as chemotherapy and radiotherapy are common treatments for malignant disease and are often coupled with hematopoietic stem cell transplant (HSCT). Delayed immune reconstitution in adults has been correlated with increased morbidity and mortality caused by infection 12, 13, 14, 15, 16, 17 and tumor recurrence 18, 19, 20. One of the most implicated predictive factors for this poor recovery is patient age. Crucial to immune recovery, therefore, is a functional thymus.
Enhancement of immune reconstitution by modulation of sex steroids
Acceleration of thymic decline at puberty is intriguing and suggests a link with increasing levels of physiologic sex steroids. Exogenous administration of sex steroids, however, in the adult causes almost total collapse of thymopoiesis through apoptosis, primarily of the immature cortical thymocytes [46]. Thymic expression of androgen receptors increases with age, and this might contribute to alterations in the downstream signaling pathways with development, which leads to sex steroid–induced
Concluding remarks
The thymus and human immune system are generally believed to have evolved to last 40–50 years. With modern advances in medicine, the average lifespan is now twice that at ∼80 years. We are therefore expecting an immune system to work beyond its ‘designed’ lifespan. As a result, with age, one becomes more susceptible to infection, chronic disease, cancer and autoimmune disorders and less able to generate protective immune responses to vaccination. These consequences can have a significant impact
Acknowledgements
We acknowledge Dr. Joseph Kaminski for expert input and advice and Dr. Laura P. Hale for thymus histology images. This work was supported in part by National Institutes of Health grants R01-AG25150 (G.D.S.), RO1-HL069929 (M.v.d.B.), RO1-CA107096 (M.v.d.B.), RO1-AI080455 (M.v.d.B.) and PO1-CA33049 (M.v.d.B.) and the Regional Biocontainment Laboratory at Duke (UC6-AI58607, GDS). Support was also received from the following organizations: the Ryan Gibson Foundation (Dallas, TX), the Elsa U. Pardee
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