Available online at www.sciencedirect.com Pleiotropic modulation of thymic functions by growth hormone: from physiology to therapy Wilson Savino 1 and Mireille Dardenne 2 In the context of the cross-talk between the neuroendocrine and immune systems, it is well known that growth hormone (GH) exerts physiological effects in central as well as peripheral compartments of the immune system.GH modulates a variety of thymic functions, including proliferation of thymocytes and thymic epithelial cells (TEC). Accordingly, GH-transgenic mice, as well as animals and humans treated with exogenous GH, exhibit an enhanced cellularity in the organ. GH also stimulates the secretion of cytokines and chemokines by the thymic microenvironment, as well as the production of extracellular matrix proteins. These effects lead to an increase in thymocyte migratory responses and intrathymic traffic of developing T cells, including the export of thymocytes from the organ, as ascertained by experimental studies with intrathymic injection of GH in normal mice and with GH-transgenic animals. Most likely, GH effects in the thymus are mediated by an IGF-1/IGF-1 receptor circuitry, which physiologically operates in nonstimulated conditions in both thymocytes and TECs. Since GH enhances thymus replenishment and increases intrathymic T-cell traffic, ultimately modulating thymocyte exit, it should be placed as a potential adjuvant therapeutic agent in the treatment of immunodeficiencies associated with thymic atrophy, and examples recently appeared in the literature are promising and strongly indicate that GH can be beneficial for individuals suffering severe immunodeficiency. Addresses 1 Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Ave. Brasil 4365, 21045-900 Rio de Janeiro, Brazil 2 Universite ´ Paris Descartes, CNRS UMR-8147, Paris, France Corresponding author: Savino, Wilson (savino@fiocruz.br, w_savino@hotmail.com) Current Opinion in Pharmacology 2010, 10:434–442 This review comes from a themed issue on Immunomodulation Edited by Vincent Geenen Available online 29th April 2010 1471-4892/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2010.04.002 In the context of the cross-talk between the neuroendo- crine and immune systems, it is well known that growth hormone (GH) exerts physiological effects in central as well as peripheral compartments of the immune system, enhancing several immune functions [1–3]. In recent years, this concept led different research groups to admin- ister GH as a coadjuvant therapeutic agent in some diseases that course with immunodeficiency. Herein, we will focus on the physiological functions of GH in the thymus, as well as its use in pathological states associated with thymic atrophy. Nevertheless, before entering into the details on how GH affects the thymus, it seemed worthwhile to provide a general background of the thymus physiology. The thymic microenvironment and intrathymic T-cell differentiation The thymus is a central lymphoid organ, where bone- marrow-derived T-cell precursors differentiate, even- tually leading to the export of mature thymocytes to the T-dependent areas of peripheral lymphoid organs. This process involves sequential expression of a variety of membrane proteins and rearrangements in T-cell recep- tor (TCR) genes. Thymocyte differentiation can be tracked by a number of membrane markers, as for example the TCR heterodi- mers, as well as the CD4 and CD8 molecules. The most immature thymocytes are TCR  CD4  CD8  (double negative for CD4 and CD8) and represent 3–5% of total thymocytes. Maturation progresses with the acquisition of TCR, CD4, and CD8 expression generating CD4 + CD8 + (double-positive) cells, which constitute 75–85% of the whole thymocyte population. At this check point, most potentially self-reactive thymocytes are negatively selected by clonal deletion, whereas a minority of devel- oping lymphocytes is rescued from death through positive selection, and progress to the CD4 + or CD8 + single- positive cells (12–15% of total thymocytes), which will be able to leave the organ, ultimately yielding the vast majority of the T-cell repertoire in the periphery of the immune system [4]. Interactions between developing thymocytes and special- ized thymic microenvironmental cells (thymic epithelial cells, dendritic cells, macrophages, and fibroblasts) sup- port and direct intrathymic T-cell differentiation by means of direct cell–cell interactions, as well as those interactions mediated by various cytokines, chemokines, thymic hormones, and extracellular matrix (ECM) [1,4,5]. Thymocytes that do not undergo productive TCR gene rearrangements die by apoptosis, whereas those expres- sing productive TCRs in their membranes interact with Current Opinion in Pharmacology 2010, 10:434–442 www.sciencedirect.com