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(Journal of Leukocyte Biology. 2002;71:381-387.)
© 2002 by Society for Leukocyte Biology

The role of growth hormone in T-cell development and reconstitution

Lisbeth A. Welniak, Rui Sun and William J. Murphy

Laboratory of Immunoregulation, NCI-Frederick and Intramural Research Support Program, SAIC, NCI-Frederick, Frederick, Maryland


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ABSTRACT
 
Growth hormone (GH), directly or through GH-induction of insulin-like growth factor (IGF)-1, has been implicated in lymphocyte development and function. Recent studies have questioned the role of GH and IGF-1 in immune responses. This review examines experimental data describing the immunoregulatory function of GH and attempts to reconcile the literature.

Key Words: neuroendocrine hormones • thymus • dwarf • deficiency


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INTRODUCTION
 
The first studies suggesting that growth hormone (GH) may have a role in the endocrine and immune systems occurred several decades ago when thymic atrophy was observed in rats following hypophysectomies (surgical removal of the anterior pituitary) [1 ]. More that 50 years later, administration of GH was used to correct lymphocyte defects in rodents lacking the anterior pituitary through surgical intervention or inherited defects [2 3 4 5 ]. Correlative associations with low or decreasing production of GH with thymic atrophy associated with normal aging have fueled the speculation that correction or augmentation of GH levels could enhance immune and particularly T-cell function.


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GH PRODUCTION AND RECEPTOR EXPRESSION
 
GH, also known as somatotropin, is a member of a family of growth factors that includes prolactin, placental lactogens, proliferins, and somatolactin. GH family members are secreted as 22–25 kDa monomers and are generally not glycosylated [6 ]. Circulating human GH includes the intact molecule as well as oligomers and two-chain isomers, a result of proteolytic cleavage. There is also a "20k" form generated by alternative splicing that may lack some GH activities [7 ]. In the serum, GH is complexed with binding proteins related to the GH-receptor extracellular domain [8 ]. GH is produced and stored in somatatrophs in the anterior pituitary [9 ] and is the major source of circulating hormone. The production of GH is pulsatile, mainly nocturnal, and is controlled by hypothalamic hormones such as GH-releasing hormone (GHRH), hypothalamic GH release-inhibiting factor, and somatostatin. Circulating levels of GH are highest in the immediate neonatal period, decreasing during childhood but peaking again during puberty. GH secretion falls precipitously during aging. GH is a diabetogenic substance, and its secretion is decreased in obesity and rises during starvation. It has been demonstrated that GH is produced by normal lymphocytes [10 11 12 13 ]. In humans, unstimulated peripheral blood lymphocytes (PBL) express GH mRNA, and up to 10% of the cells secrete biologically active protein [10 11 12 ]. B cells are the predominate source of GH mRNA, and T cells express mRNA to a lesser extent [14 ]. GH production has also been demonstrated in splenic CD4+ T cells, B cells, and macrophages of the rat [13 ].

GH stimulates the production of insulin-like growth factor (IGF)-1, which is responsible for many of the activities attributed to GH. GH also has direct effects, including lipolysis [15 ], increased amino acid transport into cells, and increased protein synthesis [16 ] as well as lactogenic effects through the engagement of the prolactin receptor [17 , 18 ].

Primate GH binds tightly to GH and prolactin receptors, whereas human prolactin can bind to the prolactin (PRL) receptor but not the GH receptor [19 , 20 ]. The murine counterparts only bind their respective receptors. Both receptors are members of a hematopoietin-receptor family, which is based on the overall homology and characteristic motifs, including two cysteine pairings and the WSXWS box in the extracellular domain. There is also limited homology in the intracellular domain among the family members [21 ]. Like other members of the hematopoietin-receptor family, engagement of the GH and PRL receptor activates JAK2 [22 ]. The GH receptor is expressed at high levels in liver and adipose tissues, although it can also be detected in other tissues in rodents, including intestine, brain, testis, heart, and skeletal muscle [8 ]. Studies performed by Gagnerault and colleagues [23 ] demonstrated in mice that the GH receptor is found on bone marrow-derived cells including CD4+CD8+ and CD8+ thymocytes as well as CD4- and CD8- thymic cells. The receptor is found at variable levels on all hematopoietic lineages in the bone marrow and on subsets of B cells, CD4+ and CD8+ T cells, and macrophages in the secondary lymphoid tissues. T-cell activation increases the proportion of CD4+ and CD8+ splenocytes expressing the GH receptor. The PRL receptor is also found on all GH-receptor positive-peripheral T cells [23 , 24 ]. In humans, tonsillar B cells express GH receptors constitutively, but the receptor was observed only on activated T cells [25 ], although another study found mRNA transcripts for GH receptors in unstimulated peripheral blood B cell, T cells, and neutrophils [14 ]. Although the GH receptor has not been characterized on natural killer (NK) cells, studies have shown that NK cell numbers and activity in patients with GH deficiency are depressed, suggesting a role for GH in NK cell biology [26 , 27 ].


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IGF-1 PRODUCTION AND RECEPTORS
 
IGF-1, known as somatomedin C, is produced in high concentrations in the liver and at lower concentrations in a variety of other tissues in response to GH. It has been shown in man that serum concentration of IGFs varies with age and physiologic condition. IGF-1 concentration is low in neonates and remains low until a peak during puberty. Serum IGF-1 along with GH decreases with advancing age. Low serum IGF-1 and IGF-2 levels are observed in GH deficiency, and excess GH results in elevated IGF-1 levels but normal levels of IGF-2. The major source of circulating IGF-1 is the liver. This source participates in the regulation of GH secretion by the pituitary, but it is not necessary for normal growth and development [28 ]. Prior to this finding, the bi-directional interaction between the liver and pituitary was thought to be necessary for normal growth. However, local tissue production of IGF-1 in response to GH has been shown to be sufficient. Similarly, although deficiency in pituitary GH may result in some aspects of immunodeficiency, local production of GH and IGF-1 may compensate. In the circulation, IGFs are complexed with binding proteins [29 ]. In the liver, IGF-I gene expression is tightly regulated by GH, whereas in nonhepatic tissues, IGF-I gene expression is regulated by tissue-specific factors in addition to GH. Rat and human leukocytes have been shown to produce IGF-1 after in vitro stimulation with GH [30 , 31 ]. As demonstrated in mice and man, macrophages are the primary source of IGF-1 in leukocytes [32 , 33 ]. Thymic epithelial cells also produce IGF-1 in response to GH, which may result in an autocrine loop because IGF-1 stimulates cell growth of the same cells [34 35 36 ]. Cells of the bone marrow microenvironment also express IGF-1 and its receptor [37 38 39 ].

The IGF-1 receptor is a member of the tyrosine-kinase growth-factor receptors and is highly homologous to the insulin receptor [40 , 41 ]. The receptor is a heterotetramer composed of two {alpha} and two ß subunits. IGF-1 receptors have been shown on the majority of B cells, NK cells, and monocytes, as well as erythrocytes [42 43 44 45 46 47 ]. Studies differ regarding the percentage of T-cell populations that express IGF-1 receptors [42 , 45 , 48 ], although the number of receptors can be influenced by the activation state of the cell [46 , 47 ]. Rat and human leukocytes have been shown to produce IGF-1 after in vitro stimulation with GH [30 , 31 ]. In the thymus, CD4-CD8- thymocytes express the highest level of IGF-1 receptors, followed by CD4+CD8+ thymocytes; lower levels of receptor expression were observed on single-positive cells [49 , 50 ]. Thus, in determining the role of GH in immune-system development and function, direct effects by GH and indirect effects through IGF-1 on particular cell types must also be taken into consideration.


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GH AND IMMUNE FUNCTION: EARLY STUDIES
 
One of the earliest associations linking GH with the thymus was the observation that thymic atrophy with aging correlated with GH-level decline. Early studies examining the role of GH on immune parameters used in vitro assays assessing the effects of GH on immune function or in vivo models of GH deficiency that occurred via surgical manipulation (hypophysectomy) or through examination of neuroendocrine hormone-deficient dwarf mice. A variety of in vitro studies have demonstrated that exogenous GH could improve a variety of immune functions including B-cell responses and antibody production [51 , 52 ], NK activity [53 ], macrophage activity [54 55 56 ], and T-cell function [53 ]. In vitro chemotaxis of monocytes as well as increases in respiratory burst activity were demonstrated after GH exposure [57 , 58 ]. NK cell-killing activity was also described as increased after GH treatment in vitro, although the mechanism remains speculative, because PRL has also been shown to increase NK function [59 ], and human GH can exert prolactinogenic effects [17 , 60 ]. GH has been shown to augment immunoglobulin production in vitro, which may also be in part a result of IGF-1, which has direct effects on B cells in vitro [61 ]. In vitro studies have also shown that GH could enhance human and murine T-cell function, as reflected by proliferation and antigen-specific responses [62 ]. Therefore, these in vitro studies indicate that GH can stimulate a variety of immune parameters by direct and indirect mechanisms (Fig. 1 ). However, many in vitro studies use fetal bovine serum in the media, which contains bovine IGF-1 and other hormones. This may result in the underestimation or overestimation of the effects of exogenous growth factors such as the GH used in the assay. In vivo studies of GH deficiency also suggested a pivotal role of GH in immune development, because initial characterization of Ames (df/df) and Snell-Bagg (dw/dw) dwarf mice indicated severe immune deficits, and some studies observed that the mice died prematurely, presumably from infection [63 ]. Both these mice fail to express the pit-1 gene product and lack developed somatotrophs (which produce GH), lactotrophs (which produce prolactin), and thyrotrophs (which produce thyroid-stimulating hormone) [64 65 66 ], although the animals are not totally devoid of these hormones, because not all nonpituitary sources of prolactin and GH are under pit-1 control. Later studies using these mice in conventional animal facilities that were specific and pathogen-free suggested that the early death demonstrated by these mice was a result of infectious agents in the facility, because again, no premature deaths were shown [67 68 69 ]. These studies clearly demonstrate the importance of housing conditions in determining the role of GH on immune parameters as well as effects of the aging process in general. Although these studies suggested that GH and possibly other neuroendocrine hormones could play a role in modulating immune development and function, they did not demonstrate an obligatory role for these hormones in immune function. There have been studies indicating that dwarf mice had impaired B-cell development and thymic hypoplasia as well as myeloid deficits [4 ]. Studies by Dorshkind and Horseman [70 ] carefully assessed the immune competence of the various hormone-deficient mice and found that T-cell function and development appeared normal with the exception of a B-cell abnormality affecting the pre-B-cell stage in development. This defect could be reversed by treatment of the mice with thyroxine, suggesting that neuroendocrine hormones could play an obligatory role in immune development [71 ]. Indeed, this deficit in B-cell progenitors may have influenced the expansion in T cells demonstrated in dwarf mice and may account for the increases shown in the aged mice [67 ]. However, the role of GH in T-cell development, particularly in the thymus, remained elusive. GH deficiency in man is not associated with gross thymic defects or T-cell deficiencies. Administration of GH to dwarf mice could restore thymic cellularity in dwarf mice, suggesting that although GH may not be an obligate T-cell growth factor, it could exert thymopoietic effects in vivo. Also complicating interpretation of the dwarf data was the observation that the time of weaning was critical in affecting the extent of thymic hypoplasia, suggesting that potential thymopoietic factors could be present in maternal milk that could compensate for the lack of GH or prolactin in these mice [72 ].



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  		Figure 1. The role of GH, IGF-1, and somatostatin, an inhibitor of GH production, on immune development. GH and IGF-1 have been shown to promote hematopoiesis, including B-cell precursors, myeloid, erythroid, and megakaryocytic lineages. NK cell development may also be promoted by GH. GH and IGF-1 can promote T-cell development in the thymus. GH and IGF-1 promote T-cell chemotaxis and may play a role in T-cell precursor immigration into the thymus and lymphocyte circulation into and between secondary lymphoid tissues. GH and IGF-1 may also promote antigen-specific immune function within the lymphoid tissues, and somatostatin may inhibit these functions. Those effects of GH, IGF-1, or somatostatin that have not yet been proven are indicated with a question mark (?).


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RECONCILIATION OF THE GH LITERATURE CONCERNING THE ROLE OF GH ON THE THYMUS
 
The conflicting data concerning the extent of thymic hypoplasia and the demonstrated susceptibility of these mice to infection led us to the hypothesis that the role of neuroendocrine hormones (i.e., GH) in the immune response may be in the protection from stress [70 , 73 ]. The thymus is exquisitely sensitive to glucocorticoids induced by stress. Therefore, multiple variables need to be taken into consideration when evaluating in vivo data concerning the role of hormones on immune parameters. These include the health status of the mouse colony [pathogens such as helicobacter and orphan parvoviruses can still be present in specific pathogen-free (SPF) colonies and manifest themselves during immune-deficiency states]; housing conditions (males often fight when housed together, resulting in injury and stress); diet; mouse strains used; influence of background genes on immune parameters; age and sex of the mice used; and whether the mice were under "resting" or unmanipulated conditions or whether they were placed under stress situations (i.e., receiving chemotherapy, tumors, etc.). All of these variables can markedly affect outcome with regard to effects on immune parameters. Dwarf mice present an excellent example about how the conclusions reached regarding the role of GH on immune parameters were critically dependent on the status of the mouse colony. Early studies demonstrated that dwarf mice succumbed to a "wasting disease," presumably infection. These studies suggested that GH played a critical role in immune function. As mouse colonies became SPF, the dwarf mice were no longer shown to present with this wasting disease and displayed modest perturbations of immune parameters [67 68 69 ]. Indeed, a recent study demonstrated that dwarf mice actually had longer life spans compared with normal littermate controls and also had improved T-cell functions as they aged [74 ]. This study would suggest that GH played a role in promoting aging and potentially inhibiting T-cell function with age. Thymic function was not assessed in this study, and only memory T cells, not naïve T cells, were increased [74 ]. However, before extrapolating these data to man, the model used and the variables associated with in vivo studies must be taken into consideration. These studies used resting dwarf mice in an SPF colony where exposure to infectious agents is minimal. Reconciling information derived from mice under these conditions with the human situation is difficult to ascertain. Therein lies a potential problem—making broad conclusions concerning immunological effects when using inbred mice under SPF conditions. Thus, depending on the conditions of the colony, the dwarf mice could die early from infection versus controls, or they could actually living longer than controls. This recent study also does not resolve the differences in results demonstrated between two laboratories characterizing the thymus of these mice when younger. It has been shown that the time of weaning can affect the extent of thymic deficiency in these mice [72 ], but the mice in the two laboratories were weaned at the same time. If the colonies were constant with regard to being pathogen-free, it was possible that housing conditions may have influenced thymic outcome. Although female mice, which do not normally engage in observable fighting behavior, were used in the studies, it was possible that the dwarf mice were "stressed" by being in the presence of the normal-sized littermates, because one group housed them with littermates, and the other did not. Therefore, an experiment was performed in which dwarf mice were housed by themselves or with their normal-sized littermates. The results indicated that simply placing the dwarf mice with their normal-sized littermates had a dramatic effect on their thymus (Table 1 ; and unpublished results). These results indicated that GH was not an obligate T-cell development factor but instead was involved in circumventing thymic responses to stress situations (i.e., corticosteroid release). Importantly, the administration of GH could reverse this susceptibility [73 ]. In fact, IGF-1 and GH have been shown to partially inhibit dexamethasone-induced apoptosis in CD4+ T cells [75 ]. It remains to be determined if an increased susceptibility to stress was a result of the absence of GH or if this phenomenon will occur in stressed mice with normal GH levels. It is also still not known whether GH provides a direct protective effect on the thymocytes or works indirectly through IGF-1, which is also known to provide antiapoptotic effects [76 , 77 ]. Alternatively, GH could promote the production of interleukin (IL)-7 or SCF from the thymic epithelial cells (Fig. 2 ). This suggests that the role of GH in the immune response may be a means to counteract the immunosuppressive effects of stress and could be of potential clinical use in that regard. Thus far, very few agents have been shown to exert thymopoietic effects in vivo. The need for the thymus to repopulate the peripheral T-cell pool in the adult has been required only recently with the advent of myeloablative therapy during bone marrow transplantation and in AIDS. Because patients in both of these instances are under stress situations, GH may be of use to augment thymic recovery in the adult.


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  		Table 1. Effects of Housing on Thymic Cellularity in Dwarf (Dw/Dw) Mice and Normal-Sized Littermates (Dw/?)



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  		Figure 2. The role of GH and IGF-1 on the thymus and thymocyte development. GH and IGF-1 are produced in the lymphoid tissue, which may result in paracrine stimulation of T-cell development. However, the primary source of circulating GH is the anterior pituitary, which is controlled through a negative-feedback loop involving IGF-1 production in the liver. Glucocorticoids can induce thymic atrophy. The mechanism by which GH protects the thymus under stress conditions is not known.


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EFFECTS OF GH ON PERIPHERAL T-CELL FUNCTION
 
GH appears to affect T-cell function by promoting thymic function and progenitor survival as well as promoting T-cell function in the periphery. GH and IGF-1 have been shown to increase T-cell functions in vitro [62 , 78 79 80 ]. GH receptors have been shown to be present on T cells, although the expression of these receptors on T-cell subsets (memory vs. naïve) or as the individual ages has not been ascertained. Another important question is the mechanism by which GH works on the T-cell response. Does GH promote the proliferation, activation, or survival of the T cell? These parameters have yet to be addressed adequately. GH has been used as an adjuvant to promote cell-mediated responses to various pathogens [53 ]. However, it is not known if these effects were directly a result of GH binding on T cells or indirect effects by stimulation of monocytes and antigen-presenting cells, because both are affected by GH in vitro [55 , 57 , 58 , 81 82 83 ]. Additionally, when human GH is used, it is possible that binding the prolactin receptor may account for the immunostimulatory effects, because prolactin has also been shown to promote T-cell function in vitro and in vivo [84 85 86 87 ]. Another means by which GH can promote T-cell responses is through effects on lymphocyte trafficking and recirculation (Fig. 1) . GH administration has been shown to promote human T-cell trafficking in immunodeficient mice [88 ]. These results suggest that clinical use of GH to promote T-cell responses may result with thymopoietic effects as well as peripheral T-cell effects being generated. It will be of interest to ascertain if GH can prevent apoptosis of lymphocytes and promote memory T-cell survival. An important caveat that needs to be addressed is the potential role of GH in promoting autoimmunity and potentially disregulating immune responses during chronic inflammation states. It will be of interest to ascertain the effects of GH administration in autoimmune-prone strains of mice or in mice receiving chronic inflammatory stimuli.


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GH AND BONE MARROW TRANSPLANTATION
 
The immune system is part of the hematopoietic system in which all lymphoid cells have arisen from a hematopoietic pluripotential stem cell (Fig. 1) . GH has been shown to promote hematopoietic growth in vitro [89 ]. One possible means by which it could affect immune-system reconstitution and development may be by promoting hematopoietic growth in vivo. We wanted to ascertain the effects of GH on hematopoietic reconstitution following syngeneic bone marrow transplant (BMT) in mice. Mice were prepared with a myeloablative dose of whole-body irradiation prior to a syngeneic BMT, followed by human GH administration at doses that did not promote weight gain. Significant effects on multilineage hematopoietic reconstitution were observed [89 ], suggesting that GH can be of use to promote myeloid recovery after BMT. These results, in combination with studies of T-cell development and immune function described above, demonstrate that GH can exert effects on immune and myeloid parameters in vivo at doses that do not exert readily observable anabolic effects. Thus, GH is pleiotropic in its effects in vivo, affecting numerous immune and myeloid lineages. Many of the observed effects on myeloid and lymphoid reconstitution may be assumed to be because of GH induction of IGF-1, given that studies have demonstrated that IGF-1 administration can exert effects on hematopoiesis and thymic reconstitution [50 , 90 ]. However, administration of prolactin also promotes hematopoietic recovery and stimulates lymphoid function [91 , 92 ]. Because human recombinant GH acts through the GH and PRL receptors and stimulates production of IGF-1, additional benefit may be provided by the use of GH over PRL or IGF-1. The use of a hormone-like GH does not appear to exert the same magnitude of effects observed when a cytokine [i.e., granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage CSF (GM-CSF)] is administered, but it appears more diverse in its outcome. This augmentation of hematopoiesis by GH may also represent another means by which GH can promote thymic recovery in that increased production of pro-T cells may occur to seed the thymus (Fig. 1) .


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POTENTIAL, CLINICAL USE OF GH TO PROMOTE IMMUNE RECONSTITUTION; OTHER CONSIDERATIONS
 
Although GH may indeed be of potential clinical use to promote T-cell reconstitution, other considerations need to be addressed. The effects of IGF-1 as a result of GH administration on tumor growth may result in higher relapse rates if GH is used to accelerate reconstitution in cancer patients receiving a BMT. Another important consideration is the end-point used in a clinical study with GH. Gross effects on T-cell counts may not be affected, and it may be critical to monitor development of naïve T-cell pools in the periphery to detect any effects of GH treatment. It is also possible that simply administering GH alone cannot restore thymic function in elderly individuals. We need more research to understand the aging process of the thymus and the role of GH in protecting the thymus from stress.

Thus, the data from pituitary-deficient and hormone or hormone-receptor animals and man suggest that GH is not an obligate factor in T-cell or other immune-cell development. However, although GH is not necessary for normal development, it does appear that GH can enhance T-cell survival and thymic function in times of stress and may therefore be of use in immune-deficiency states to promote immune development and function.


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ACKNOWLEDGEMENTS
 
This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Health Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.


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FOOTNOTES
 
Correspondence: William J. Murphy, Ph.D., Intramural Research Support Program, SAIC, Bldg. 567, Room 210, Frederick, MD 21702. E-mail: murphyw@ncifcrf.gov

Received October 24, 2001; revised December 4, 2001; accepted December 5, 2001.


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