Ghrelin promotes thymopoiesis during aging

Abstract

The decline in adaptive immunity, T lymphocyte output, and the contraction of the TCR repertoire with age is largely attributable to thymic involution. The loss of thymic function with age may be due to diminished numbers of progenitors and the loss of critical cytokines and hormones from the thymic microenvironment. We have previously demonstrated that the orexigenic hormone ghrelin is expressed by immune cells and regulates T cell activation and inflammation. Here we report that ghrelin and ghrelin receptor expression within the thymus diminished with progressive aging. Infusion of ghrelin into 14-month-old mice significantly improved the age-associated changes in thymic architecture and thymocyte numbers, increasing recent thymic emigrants and improving TCR diversity of peripheral T cell subsets. Ghrelin-induced thymopoiesis during aging was associated with enhanced early thymocyte progenitors and bone marrow-derived Lin -Sca1 + cKit + cells, while ghrelin-and growth hormone secretagogue receptor-deficient (GHS-R-deficient) mice displayed enhanced age-associated thymic involution. Leptin also enhanced thymopoiesis in aged but not young mice. Our findings demonstrate what we believe to be a novel role for ghrelin and its receptor in thymic biology and suggest a possible therapeutic benefit of harnessing this pathway in the reconstitution of thymic function in immunocompromised subjects. IntroductionThe thymus is critical for the development, selection, and maintenance of the peripheral T cell pool possessing a broad spectrum of TCR specificities. The mammalian thymus is capable of generating T cells throughout the life span. However, after puberty and with advancing age, the thymic space becomes progressively filled with adipocytes coupled with a dramatic loss of thymocytes in the cortical and medullary areas, leading to a reduction in output of naive T cells. This process is called as thymic involution (1).The lack of a thymus in humans (DiGeorge syndrome) and thymectomy of neonatal mice lead to severe immunodeficiency due to paucity of mature T cells. During physiological aging, the total peripheral T cell pool is maintained by homeostatic expansion of preexisting T cells rather than replenishment by thymic export (2). Consequently, the long-lived naive T cell repertoire is reduced with an expansion of memory phenotype T cells, thereby limiting a host's ability to mount responses against new antigenic challenges. It has been demonstrated that defects in naive CD4 + T cells are also due to the chronologic age of the naive cells themselves rather than the chronologic age of the host (3). Involution of the thymus with age and lack or paucity of newly formed naive CD4 + T cells is therefore believed to be responsible for much of the deterioration in adaptive immunity and the resultant immune dysfunction in the elderly (4). However, several recent studies have demonstrated that the old thymus still retains the capacity for T cell lymphopoiesis with the ability to mount functional immune responses, albeit to a lim...

Distinct effects of obesity and puberty on risk and age at onset of pediatric MS

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“…Obesity is associated with a change in adipokine profiles including an increase in leptin which plays a proinflammatory role, and lowered ghrelin which is anti‐inflammatory. These adipokines play varied role in thymic maturation, T‐cell proliferation, development of memory cells and cytokine production,17, 28, 29, 30, 31 all mechanisms which are purported to play a role in pediatric‐onset MS 32, 33, 34, 35…”

Effect of acute and regular exercise on growth hormone secretagogue receptor-1a expression in human lymphocytes, T cell subpopulation and monocytes

“…Indeed ghrelin and GHS-R1a knockout mice exhibit reduced thymocyte counts and more pronounced age-dependent thymic involution than in wild type mice (Dixit et al, 2007). Ghrelin expression by T cells is also reduced in ageing mice and ghrelin infusion in this model has been shown to reduce levels of IL-6, TNF-α and IL-1β (Dixit et al, 2009).…”

Impact of the Somatotrope Growth Hormone (GH)/Insulin-Like Growth Factor 1 (IGF-1) Axis Upon Thymus Function: Pharmacological Implications in Regeneration of Immune Functions

“…Interestingly, treatment of SCID mice with a GH secretagogue (GHS) results in increased thymic cellularity and differentiation, as well as in promoting thymic engraftment in bone marrow transplant [120]. Furthermore, ghrelin, a potent GH secretagogue, can also promote T-cell output from an aging thymus [121]. Also in primary immunodeficiencies, manipulation of the somatotrope GH/IGF-1 axis offers promising results.…”