Thymus formation and maintenance are under the physiological control of several growth factors including GH and IGF-I. GH is typically produced by several different cell types including thymocytes and TEC, which also express the corresponding receptor, GHR. Hence, GH acts on these cells in an autocrine fashion influencing cell growth, cell proliferation and the cytoskeleton. GH also evokes the synthesis of IGF-I which acts as a primary mediator of the biological effects of GH. IGF-1 may indirectly affect the frequency of T cell precursors as IGF-1 has been implicated in the expansion of primitive multilineage hematopoietic progenitor cells [29
], in their lineage decisions [30
] and in the regulation of hematopoietic stem cell accumulation and differentiation by osteoblastic niche cells [31
The role of GH as a growth factor influencing thymus size was initially suggested in anterior hypopituitary (i.e. GH-, thyroxine- and prolactin-deficient) Snell-Bagg mice under stress and in hypophysectomized rats since both conditions cause an early, progressive thymus involution [32
]. The therapeutic benefits of this polypeptide as an immunostimulator was demonstrated in studies where an increased thymic cellularity, improved numbers of recent thymic emigrants and a broader TCR repertoire among peripheral T cells was noted in hypopituitary mice substituted with recombinant GH and in old, wild type animals treated with the GH secretagogue ghrelin [36
]. GH also accelerates thymocyte recovery and the reconstitution of the peripheral T cell compartment in lethally irradiated mice engrafted with allogeneic T cell-depleted bone marrow cells [38
]. However, GH per se is not required for normal thymopoiesis because GH-deficient mice housed under stress-free conditions display a regular lymphoid development [39
Studies in humans have recently established the clinical benefit of recombinant GH to enhance thymic function in adults with thymus atrophy. Treated with a highly active antiretroviral therapy (HAART) and daily subcutaneous GH injections, HIV infected adults reveal an increased thymic mass, an improved T cell output and higher numbers of circulating naïve and total CD4+
T cells when compared to patients treated only with HAART [40
]. Notably, the withdrawal of GH in adults with a GH deficiency mirrors these observations as the interruption of GH substitution swiftly decreases the frequency of recent thymic emigrants.
The resumption of GH replacement in these patients is then also followed by a significant rebound in the thymic export of new T cells [41
]. Both of these studies demonstrate in addition a positive correlation between the frequency of recent thymic emigrants and plasma IGF-I concentrations. As TEC express both IGF-I and IGF-I receptor in response to GH [42
], the stimulatory effect of GH on these cells is likely accomplished by engagement of an IGF-I/IGF-I receptor-mediated circuit.
The potential of IGF-I as a therapeutic agent to stimulate thymopoiesis was suggested by several independent observations: young mice transgenic for IGF expression have a hypercellular thymus [43
]; thymus organ cultures in which IGF-I or its receptor are neutralized demonstrate an early block in thymocyte maturation [44
]; and the administration of recombinant IGF-I to naïve mice stimulates the proliferative expansion of thymocytes, which in turn results in an increased number of recent CD4+
thymic emigrants [45
]. IGF-I also increases the number of circulating T cell precursors (defined as lineage negative, c-kit- and Sca-1-positive cells, i.e. LSK cells) following their exit from the bone marrow. This activity likely contributes to the thymus stimulatory effect of IGF-I. In parallel, IGF-I treatment enhances the number of cortical and medullary TEC possibly generating a bigger stromal scaffold to accommodate thymopoiesis. However, IGF administration alone does not fully restore thymic involution [46
The role of IGF-mediated signaling in averting thymus atrophy is clearly more complex than previously acknowledged since a deficiency in the pregnancy-associated plasma protein A (PAPPA) also mitigates thymus involution [47
]. PAPPA acts as a metalloproteinase catalyzing the release of IGF-I from its binding protein, IGF-BP4, and an engineered deficiency of this enzyme results in a slower delivery and a lower tissue availability of IGF-I. It is therefore surprising that PAPPA-null animals resist age-dependent thymic atrophy. Moreover, these mice have an increased frequency of bone marrow resident T cell progenitors [47
], which may increase the availability of these cells for thymopoiesis although their developmental potential and survival still need to be determined. The molecular mechanisms by which a limited bioavailability and hence attenuated IGF-I signaling in PAPPA-deficient mice increases the resistance to age-related thymus atrophy is however not yet known.