Rejuvenation of the aging T cell compartment

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The elderly face significant risk for susceptibility to infection and cancer because of declining immune function. Various agents used in the setting of bone marrow transplantation and aging studies represent promising approaches to combating T cell defects in the aging population. Preclinical and clinical studies on the T cell reconstitution effects of sex steroid ablation, keratinocyte growth factor, the growth hormone pathway, and the cytokines interleukin-7, interleukin-12, and interleukin-15 indicate that these strategies may be used to alleviate the effects of T cell deficiencies in the elderly.

Introduction

Immune function decreases with age, owing to quantitative and qualitative changes in the cells of the immune system and their niches. The deleterious effects of aging on the T cell compartment are well studied as they lead to increased susceptibility to infection, decreased immunosurveillance of malignant cells, and difficulty in establishing protective immunity via vaccination. Aging reduces the number and T cell potential of hematopoietic precursors, and involution of the thymus renders it less capable of supporting de novo T cell development. Consequently, aging compromises the functional capacity of lymphocytes, resulting in a T cell pool with restricted receptor specificity and fewer naïve T cells [1, 2]. These effects are reviewed in depth elsewhere in this issue, and we will concentrate instead on strategies to boost T cell function in aging individuals.

The conditioning regimens for hematopoietic stem cell transplantation (HSCT) cause significant damage to recipient thymi, resulting in prolonged post-transplant T cell deficiency [3]. Studies in experimental mouse models of HSCT have identified agents that are relevant for boosting T cell reconstitution not only after transplant, but also potentially in aging recipients.

Reviewed below are studies in older and transplanted mice, which elucidate mechanisms for improving T cell development.

Section snippets

Sex steroid ablation

Sex steroids are known to negatively regulate the development of immune cells. The increase in sex steroids at puberty corresponds to the dramatic involution of the thymus at this time. Accordingly, prepubescent castration to reduce sex steroid levels prevents thymic atrophy and postpubescent castration reverses thymic atrophy while enhancing T cell numbers in the periphery [4, 5, 6, 7, 8, 9]. Murine models of autologous and allogeneic HSCT have indicated that the surgical castration of

Keratinocyte growth factor (KGF)

KGF, also called fibroblast growth factor 7, mediates the proliferation and differentiation of epithelial cells, including thymic epithelial cells (TECs), which express the KGF receptor FGFR2IIIb [14]. Thymic fibroblasts, mesenchymal cells, and thymocytes can produce KGF [15, 16, 17]. KGF administration can protect the thymus from damage, and enhance T lymphopoiesis in young and old mice [18].

KGF−/− mice do not have thymic defects, but display impaired T cell reconstitution following sublethal

Growth hormone (GH), insulin growth factor-1 (IGF-1), and ghrelin

GH is produced primarily by the pituitary, but it can also be produced by hematopoietic cells [25, 26, 27, 28]. GH receptor is expressed on thymocytes, peripheral T cells, and various other cells of hematopoietic origin [29, 30, 31, 32]. Aging humans have lower serum levels of GH, as well as IGF-1, a downstream target of GH signaling [33]. GH effects are mediated in large part via IGF-1 induction, although GH may also act directly to improve immune reconstitution [33]. The IGF-1 receptor is

Interleukin (IL)-7, IL-12, and IL-15

IL-7 and IL-15 are common cytokine γ chain receptor cytokines, with various stimulatory effects on lymphocytes. IL-7 is produced by stromal cells throughout the body, including thymic stroma [46]. Signaling induced by IL-7 supports thymocyte development, and peripheral T cell survival and proliferation [47, 48, 49, 50, 51]. The administration of IL-7 to aging individuals and individuals with thymic damage caused by chemotherapeutic or radiation-based conditioning for bone marrow transplantation

Conclusion

Recent mechanistic and clinical studies have defined strategies that could enhance T cell immunity in aging individuals (summarized in Figure 1). These approaches enhance the number of T cell precursors (sex steroid ablation), promote thymopoiesis (sex steroid ablation, KGF, GH, IGF-1, ghrelin, IL-7, IL-15, and IL-12), and peripheral T cell numbers (sex steroid ablation, KGF, GH, IGF-1, ghrelin, IL-7, and IL-15), survival (GH, IGF-1, ghrelin, IL-7, and IL-15), repertoire (sex steroid ablation,

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This research was supported by the National Institutes of Health grants RO1-HL069929 (MvdB), RO1-CA107096 (MvdB), RO1-AI080455 (MvdB), and PO1-CA33049 (MvdB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Support was also received from the US Department of Defense: USAMRAA Award W81XWH-09-1-0294 (MvdB), Ryan Gibson Foundation, the Elsa U. Pardee Foundation, the Byrne Foundation, the Emerald

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