displayed a smaller (31%) decrease in total T-cell number [39]. The same experimental model provided evidence that IGF-1 preferentially exerts mitogenic effects on most immature CD42CD82 T cells, and inhibits commitment from the CD42CD82 to the CD4+CD8+ stage. Therefore, it clearly appears that most of the GH thymotropic actions evidenced by others and by the present study are not a direct effect but are essentially mediated by local IGF-1 signaling between thymic stromal cells and precursor T cells during their differentiation in the thymus. Further supporting this view, a very recent study has elegantly demonstrated that exogenous IGF-1 increases peripheral naive and recent thymic emigrants populations, and that the control of thymic function predominantly involves TEC expansion regulating thymocyte precursor entry and facilitating intrathymic T-cell proliferation [40]. Interestingly, the effects reported in that study were observed after IGF-1 administration for 14 days, a time period which suggests that IGF-1 thymotropic action needs intervention of local intrathymic mediators. Such findings raise the question about the mediation of cytokines/chemokines produced by TEC and whose identity remains to be further deciphered although interleukin 7 (IL-7), a cytokine constitutively produced by TEC, appears as one plausible candidate [41]. The impact of GH on the intrathymic generation of TCR diversity may also be addressed though this question was not addressed in our study. This is however a very important question, and a recent study nicely showed that infusion of ghrelin, a natural GH secretagogue, into old mice reverses the age-related changes in thymic morphology and thymocyte numbers, but also increases thymic output of naive T cells and improves TCR diversity of peripheral T cell subpopulations [27]. 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There is less and less doubt that endocrine-based therapies aimed at enhancing thymic function might be of very great help in the future to correct this age-related decline in immunocompetence and to assist senior people in their fight against infectious diseases. Supporting Information Checklist S1 CONSORT checklist Found at: doi:10.1371/journal.pone.0005668.s001 (0.05 DOC) Protocol S1 Trial Protocol Found at: doi:10.1371/journal.pone.0005668.s002 (0.03 DOC) MB MB Acknowledgments We thank all patients included in this study for their participations. We are grateful to Elisabeth Lallemand for blood sample collection. We are grateful to J.M.McCune for his helpful comments. Note This study has been selected for oral presentation at the 2009 Meeting of the Endocrine Society - Washington, DC Author Contributions Conceived and designed the experiments: GM HJM VG. Performed the experiments: GM HK. Analyzed the data: GM HK JJL MM HJM VG. 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