Ghrelin promotes thymopoiesis during aging
Vishwa Deep Dixit, … , Roy G. Smith, Dennis D. Taub
Vishwa Deep Dixit, … , Roy G. Smith, Dennis D. Taub
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):2778-2790. https://doi.org/10.1172/JCI30248.
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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.

Authors

Vishwa Deep Dixit, Hyunwon Yang, Yuxiang Sun, Ashani T. Weeraratna, Yun-Hee Youm, Roy G. Smith, Dennis D. Taub

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Figure 9

Lack of ghrelin signaling reduces thymopoiesis.

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Lack of ghrelin signaling reduces thymopoiesis. (A) Compared with WT lit...
(A) Compared with WT littermates, the 24-month-old ghrelin and GHS-R knockout mice had reduced TREC+ RTEs. *P < 0.05. (B) Ghrelin–/– and GHS-R–/– mice demonstrated a marked decrease in LSK in bone marrow. GHS-R–deficient mice show a marked decline in TCR repertoire in peripheral CD4+ cells with age. (C) CDR3 size spectratyping was used to analyze the TCR repertoire. Total RNA from splenic CD4+ cells was reverse transcribed and amplified by PCR with 23 pairs of TCR-BV– and FAM-labeled Cβ-specific primers. Results are shown for Vβ families showing major perturbation as a density peak histogram. CDR3 sizes are shown on the x axis, and peak fluorescence intensity is shown on the y axis. Results are representative of 4 experiments. The Vβ7, -11, -13, and -19 of GHS-R–/– mice displayed a markedly monoclonal spectratype (marked increase in the intensity of single peak/band), while Vβ1, -3.1, -5.2, -6, -8.1, -10, -14, and -15 showed a typical oligoclonal pattern and distortion from Gaussian distribution. Interestingly, none of GHS-R–/– mice had amplification of Vβ9 compared with WT littermates.