Hormonal control of T-cell development in health …...Hormonal control of T‑cell development in...

Once formed in the thymus, mature T cells migrate to peripheral lymphoid organs to initiate the cell- mediated immune response. Importantly, hormones can control thymus physiology, including T-cell devel-opment, and the thymus itself can also affect endocrine axes1. Investigations in the 1970s and 1980s showed that neo natal thymectomy generated abnormal devel-opment of secondary sexual organs2, and that a given cell-mediated antigen stimulation triggered a feedback response invol ving the production of glucocorticoids and IL-13. During the 1980s, the existence of a com-mon syntax in neuro endocrine and lymphoid tissues was also proposed4. Accordingly, immune cells can produce and release mol ecules classically defined as hormones, and cells of the nervous and endocrine tissues also produce cytokines5.

In pioneering work, stress-induced activation of the hypothalamus–pituitary–adrenal axis was shown to trigger severe atrophy of the thymus6. Since this research was published, the cross-talk between the immune and neuroendocrine systems has been ext ended to other endo crine axes, including those medi-ated by the inter actions between lymphocytes and micro-environmental cells in the thymus, spleen and lymph nodes and hormones secreted by the hypothalamic–pituitary–gonadal, hypothalamic–pituitary–thyroid

and hypothalamic–growth-hormone/prolactin axes. Additionally, the nervous system can influence the thymus via direct innervation of blood vessels and parenchymal cells, which has been reviewed elsewhere7.

Given the variety of interactions between neurons, endocrine and immune cells, that dysfunctions in one of these systems can affect the other is unsurprising, and can lead to diseases such as those observed during ageing and several infectious diseases, such as Chagas disease and malaria. In this Review, we describe the effects of hormones of the functioning of the thymus, as well as their role in T-cell development in both healthy and diseased states.

T‑cell developmentThe entire process of T-cell differentiation takes place within a 3D network called the thymic microenviron-ment (FIG. 1). This network is composed of non lymphoid cells (such as thymic epithelial cells (TECs)), extra cellular matrix and soluble moieties such as cyto kines or chemo-kines, as well as classic thymic hormones such as thymu-lin, thymo poietin and thymosins8,9. Other hormones, including growth hormone (GH), prolactin, oxytocin and glucocorticoids, which are pro duced by the endo-crine glands such as the pituitary gland and the adrenals, are also involved in this thymic microenvironment10–12.

1Laboratory of Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Avenue Brasil 4365, 21045-900, Manguinhos, Rio de Janeiro, Brazil.2Hôpital Necker, CNRS UMR 8147, Université Paris Descartes, 75015 Paris, France.

Correspondence to [email protected]

doi:10.1038/nrendo.2015.168 Published online 6 Oct 2015

Hormonal control of T‑cell development in health and diseaseWilson Savino1, Daniella Arêas Mendes-da-Cruz1, Ailin Lepletier1 and Mireille Dardenne2

Abstract | The physiology of the thymus, the primary lymphoid organ in which T cells are generated, is controlled by hormones. Data from animal models indicate that several peptide and nonpeptide hormones act pleiotropically within the thymus to modulate the proliferation, differentiation, migration and death by apoptosis of developing thymocytes. For example, growth hormone and prolactin can enhance thymocyte proliferation and migration, whereas glucocorticoids lead to the apoptosis of these developing cells. The thymus undergoes progressive age-dependent atrophy with a loss of cells being generated and exported, therefore, hormone-based therapies are being developed as an alternative strategy to rejuvenate the organ, as well as to augment thymocyte proliferation and the export of mature T cells to peripheral lymphoid organs. Some hormones (such as growth hormone and progonadoliberin-1) are also being used as therapeutic agents to treat immunodeficiency disorders associated with thymic atrophy, such as HIV infection. In this Review, we discuss the accumulating data that shows the thymus gland is under complex and multifaceted hormonal control that affects the process of T-cell development in health and disease.

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Lymphocyte precursors that originate from the bone marrow enter the thymus through postcapillary venules located close to the cortico-medullary region of thymic lobules (FIG. 1a)13. Developing thymocytes differen tially express molecules that characterize well-defined stages of normal T-cell development. Among these mol ecules, the expression of the T-cell receptor (TCR) at the membrane, together with the accessory receptors CD4 and CD8, can be used to trace intrathymic differenti ation, particularly by using cyto-fluorometry. The TCR is a hetero dimer (mostly formed by one α and one β chain) that results from somatic recombination of distinct gene segments (known as V, D and J)14. Such a mechanism enables the generation of a vast number of distinct TCR, which collectively form the T-cell repertoire. Up to 1020 events of recom-bination can occur during thymus selection, which is associated with the generation of 108 T cells in mice and 1012 T cells in humans15.

Most immature thymocytes express neither the TCR, nor CD4 and CD8, and are called double-nega-tive (DN) thymocytes, as they lack both CD4 and CD8 on their membranes. Cells that start to express both CD4 and CD8 co-receptors become double-positive (DP). At this stage, developing thymocytes express low levels of the membrane TCR, and can be pheno-typed as TCRlowCD4+CD8+16. These thymocytes occupy most of the cortical region of thymic lobules. During this phase, DP cells undergo positive selec-tion, which enables cells that express TCRs to interact with the microenviron mental cells and continue dif-ferentiation, whereas those that do not express TCRs undergo apoptosis17.

As thymocytes differentiate further, these cells enhance the expression of TCR and cease to express either CD4 or CD8, thereby becoming single- positive (SP) cells with the phenotypes of either TCRhighCD4+CD8– or TCRhighCD4–CD8+18. These SP cells undergo apoptosis if they have a high or very low avidity when interacting with a TCR and the endogen-ous peptide coupled to major histocompatibility com-plex (MHC) class I or class II molecule expressed by microenvironmental cells in the thymus (particularly TECs and thymic dendritic cells (TDCs))17,19,20.

In the medulla of the thymus, peripheral tissue antigens (PTAs) are expressed by TECs21. These PTAs are proteins or peptides specifically expressed in given tissues of the body that represent self-antigens of most paren chymal organs, such as insulin, which is expressed by the endo crine cells of pancreatic islets of Langerhans. PTA expression is controlled by AIRE expression, which enables the presentation of self-peptides by medullary TECs (mTECs) to developing thymocytes22,23. This process avoids the development of self-antigen reactive cells and consequently prevents autoimmunity. Mature SP thymocytes that have survived this negative selec-tion process can ultimately emigrate from the thymus towards secondary lymphoid organs (that is, the spleen, lymph nodes, tonsils and appendix) and constitute the peripheral pool of T lymphocytes (FIG. 1a)24,25.

During differentiation, thymocytes migrate within the thymic lobules. DN cells are found in the sub-capsular outer cortex of the thymic lobules, whereas DP cells are found in the inner cortex and mature SP thymocytes are located in the medulla (FIG. 1a)24,25. Developing thymocytes interact with different compo-nents of the thymic microenvironment in various ways including by direct cell–cell interaction, as well as with extra cellular matrix and soluble moieties, such as cytokines, chemo kines, sphingolipids and hormones (FIGS 1b,2)26–28. In early intrathymic T-cell development, a key cell–cell interaction is mediated by neurogenic locus notch homo logue protein 1 (commonly known as Notch), which is expressed by T-cell precursors, and the protein Delta-like protein 4 (Dll4), expressed by the thymus epithelium29. Disruption of Dll4 expression in TEC completely impedes thymopoiesis30.

The thymus undergoes physiological age-dependent atrophy, owing to the depletion of developing thymo-cytes, together with changes in the microenvironmen-tal com partments, and infiltration with adipose tissue, particularly secondary to fibroadipogenetic transfor-mation31–33. The cortico-medullary tissue architecture is progressively lost, which occurs in parallel with a decline in the export of thymocytes34. This process affects the peripheral T-cell compartment, with a consequent decrease in immuno responsiveness as an indivi dual ages35. In addition, the epithelial compartment of ageing mice is altered in both cortical and medullary regions, with reduced numbers of TECs (including mTECs expressing AIRE) and conse quently reduced expression of PTAs36,37, which in theory favours the generation of autoimmune events in ageing individuals. The molec-ular mechanisms underlying age- dependent thymic atrophy are not fully understood. Even so, a number of pre-clinical and clinical approaches to rejuvenate the organ have already been developed that result in sub-stantial improvement in thymus function, such as sex steroid ablation and administration of GH and IL-734,38.

Thymic hormone‑mediated circuitsHormonal control of the thymus includes both endo crine and paracrine/autocrine pathways that act on thymic microenvironment cells and thymocytes via specific hormone receptors. Accordingly, hormones regulate

Key points

• The thymus is the primary lymphoid organ responsible for the generation of T cells

• Thymus physiology and T‑cell development can be controlled by hormones, via a variety of endocrine and paracrine pathways

• Microenvironmental cells in the thymus constitutively produce hormones that are typically secreted by the pituitary gland, such as growth hormone, prolactin, oxytocin and vasopressin

• Glucocorticoids induce thymocyte depletion through caspase‑dependent apoptosis, whereas growth hormone enhances thymocyte proliferation and migration

• Considering the variety of the interactions between the endocrine, the nervous and the immune systems, dysfunctions in one of these systems can affect the other

• Acute infection by Trypanosoma cruzi (the causative agent of Chagas disease) induces thymic atrophy through glucocorticoid‑mediated thymocyte depletion, which can be counteracted by exogenous prolactin

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the proliferation and survival of both lymphoid and thymic microenvironment cells, as well as selection of the T-cell repertoire, which is a mechanism partly related to the modulation of TCR activation upon MHC-peptide binding39. Many different hormones also regulate the migration and export of developing T cells (TABLES 1,2)8.

The hypothalamic hormones that affect the thymus are peptides derived from specialized neurons in specific hypothalamic nuclei, where axonal processes release the hormonal content in a specialized vascular network that

enables their action in the anterior pituitary (also known as the adenohypophysis) gland40. Hormones secreted by the adenopituitary gland can directly stimulate other endo-crine targets to release hormones and affect tissue growth, as observed for many aspects of thymic physiology (FIG. 2).

GH–IGF‑1Isolated ex vivo human thymocytes and primary TEC cultures can produce and secrete GH41. The expression of GH receptor was initially reported in cultured human

Positiveselection

Negativeselection

Highproliferation

Very lowproliferation

Blood vessel

Dendritic cell

Macrophage

SP CD8+

SP CD4+

DP

DN

Cortical TEC

Medullary TEC

Cytokine/hormone receptor

Integrin-type membrane receptor

Delta-like protein 4

Cytokine, peptidic hormone

G protein-coupled receptor

Chemokines

Laminin, fibronectin

TCR–MHC complex

Notch

b

a

Cortex

Cortico-medullary

junction

Medulla

1

3

4

5

2

Nature Reviews | EndocrinologyFigure 1 | Intrathymic T‑cell differentiation. a | T-cell progenitors enter the thymus via post-capillary venules in the cortico-medullary region of the thymus lobules and pass through distinct microenvironment regions: the outer cortex, followed by the inner cortex and finally the medulla. The thymocytes interact with cells in the thymus microenvironment such as cortical TECs, medullary TECs, dendritic cells and macrophages. Developing T cells also regulate the expression levels of different proteins, such as the TCR heterodimer, the CD3 complex, CD4, CD8, CD24, CD25, CD44, CD69 and CD62L, which can be used as markers to define a given stage of development within the organ. b | Cells of the thymus microenvironment interact via multiple mechanisms including: via the TCR and MHC/endogenous peptides (1), direct cell–cell interaction such as Notch or Delta-like protein 4 (2), the extracellular matrix, such as laminins and fibronectin, which bridge thymocytes to TEC via integrin-type membrane receptors (3), chemokines and other soluble moieties that activate G protein-coupled receptors (4) and via cytokines and peptidic hormones, such as IL-1, IL-7, growth hormone and prolactin (5). Abbreviations: DN, double negative; DP, double positive; MHC, major histocompatibility complex; TEC, thymus epithelial cell; TCR, T-cell receptor; SP, single positive.

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TECs42 and confirmed with the co-localization with cyto keratin labelling in avian thymus43. Expression of GH receptor is particularly evident in immature thymo cytes, as seen in both mice and humans41,44.

Several functions in the thymus are controlled by GH45. Transgenic mice that overexpress GH have an enlarged thymus, and similar effects have been observed in mice and humans treated with recombinant forms of the hormone46–48. GH can also modulate the thymic micro environment by increasing the secretion of cytokines, chemokines and thymulin41. Interestingly, patients with acromegaly have high serum levels of thy-mulin compared with age-matched healthy individu-als or patients with acromegaly who have been treated by pituitary surgery or octreotide49. Nevertheless, the

structure of the thymus in these patients has not been evaluated by noninvasive methods. However, in one case reported in the literature, a patient with acro-megaly who had high levels of GH and insulin-like growth factor 1 (IGF-1) presented with thymic hyper-plasia, as ascertained by radiological examination and CT scanning50.

GH also enhances the deposition of proteins involved in cell migration, such as laminin species and stromal cell-derived factor 151,52. The migration of thymocytes derived from GH transgenic mice or from mice injected with GH directly into the thymus, is enhanced towards sources of stromal cell-derived factor 1 and laminins51,52. Interestingly, the number of cells derived from the thy-mus are also increased in peripheral lymphoid organs in both of these mouse models52. This finding suggests that GH induces changes in the repertoire of both thymic and peripheral T cells, although no experimental data yet supports this assertion.

A large proportion of GH effects in the body are mediated by the production and release of IGF-1. Thymic cells can produce and release IGF-1, and also express the corre sponding receptor, IGF1R53. Moreover, the enhan-cing effects of GH upon thymulin production, extra-cellular matrix expression and adhesion of developing thymo cytes to TECs can be abrogated by treating cells with GH, IGF-1 and IGF1R antibodies41,53.

Although the stomach is considered to be the major source of peripheral ghrelin, this hormone is also expressed in immune cells and regulates T-cell activation and inflammation54. Ghrelin promotes the release of GH by acting on a specific G protein- coupled receptor: the GH secretagogue receptor type 1 (GHS-R)55. GHS-R mRNA and the protein have also been shown to be present on human and rodent T cells; acylated and des-acyl ghrelin are also produced and secreted upon T-cell activation54. GHS-R is expressed in the thymus and the various thymocyte subsets, with the highest expression in DP cells, and expression is also decreased during ageing56. Functionally, infusion of ghre-lin into aged mice led to recovery of the age-associated changes in thymic architecture and increased numbers of early thymocyte progenitors, which resulted in augmen-tation of thymo cyte numbers as well as recent thymic emigrants in the periphery56.

Receptors for GH, prolactin and leptin belong to the class I cytokine receptor superfamily, and are com-posed of an extracellular ligand binding domain, a trans membrane domain and an intracellular domain57. These receptors lack intrinsic kinase activity and trans-duce signals through kinases that interact with its cyto-plasmic tail. The main signalling pathway activated by these receptors is the Janus kinase/signal transducer and activator of transcription (STAT) pathway (FIG. 3). Binding of the ligand induces the dimerization of the receptor and activation of Janus kinase 2 (JAK2), which in turn phosphorylates multiple tyrosine residues, enabling the binding of STAT1, STAT3 and STAT558. Tyrosine-phosphorylated STAT5 dissociates from the receptor, dimerizes and translocates to the nucleus, where it binds to the promoters of target genes.

Higher brain centres

AdrenalsOvariesThyroid

T3T4

E2 GCProg

TSH FSHLH

Progonadoliberin-1CRH GHRH

TRH

ACTH APVOT

GHPRL

Epi ACh NE

Spinalcord

DRG

Hypothalamus

Anterior pituitary

Nerve endings

Posterior pituitary

Thymus

Cortex

Cortico-medullary

junction

Medulla

Nature Reviews | EndocrinologyFigure 2 | Immuno–neuro–endocrine interactions in the thymus. The thymus can be influenced by both peptide and nonpeptide hormones. The neuroendocrine control of the thymus includes sympathetic and parasympathetic innervation of the organ, with local release of neurotransmitters such as NE and ACh. Abbreviations: ACh, acetylcholine; ACTH, adrenocorticopropic hormone; AVP, arginine vasopressin; CRH, corticotropin-releasing hormone; DRG, dorsal root ganglion; E

2, estradiol;

Epi, epinephrine; GC, glucocorticoid; GH, growth hormone; GHRH, GH-releasing hormone; LH, luteinizing hormone; NE, norepinephrine; OT, oxytocin; PRL, prolactin; Prog, progesterone; TRH, thyrotropin-releasing hormone.

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ProlactinDeveloping thymocytes constitutively produce prol-actin59 and mTECs seem to be the main source of this protein60. We have also shown that prolactin receptor is expressed on mTECs and their activation leads to the proliferation of this cellular subset61. Moreover, most thymic dendritic cells express the PRLR gene (which encodes the pro lactin receptor), and when these cells are treated with prolactin they increase responsiveness in allogeneic mixed leukocyte reactions62. Such an effect is probably related to the upregulation of MHC surface expression and the co-stimulatory molecule CD8063.

PRLR is also expressed by thymocytes, and this expres-sion is independent of the thymocyte maturation stage and prolactin receptor expression increases in response to stimulation with mitogenic factors such as con-cavalin A64,65, as well as high levels of prolactin66. Despite normal development of the immune system in mice defi-cient in the production of prolactin67,68 or expression of PRLR69, prolactin has been shown to be an important fac-tor for both survival and proliferation of early T-cell pre-cursors such as CD25+CD4–CD8– DN cells63. Accordingly, monoclonal antibodies against prolactin and the prolactin receptor block T-cell development, which leads to accu-mulation of DN cells in the thymus63. These data indicate that prolactin contributes to the physiological modula-tion of thymus function, but is not essential for thymus development. Furthermore, prolactin seems to counteract

the immunosupressive effects of gluco corticoids on the thymus under stress conditions, as demonstrated by different in vivo models in which an increase in circu-lating levels of prolactin protected thymocytes from glucocorticoid-induced apoptosis60,70.

NeuropeptidesThymus physiology is also influenced by neuropeptides such as oxytocin and vasopressin, which are released by the posterior pituitary lobe (known as the neuro-hypophysis) in the brain71,72. TECs produce both vaso-pressin and oxytocin, but no vasopressin production has been detected in thymocytes12. The G protein-coupled oxytocin receptor has been detected in all thymocyte subsets, whereas the vasopressin V1b receptor was only found in DP and CD8+ SP cells12,72,73. Functionally, inhib-ition of the oxytocin receptor in fetal thymus organ cul-tures increases the amount of early apoptosis of CD8+ mature T cells, while vasopressin V1b receptor antag-onists, such as nelivaptan, inhibited T-cell differenti-ation and favoured the development of CD8+ T cells72,74. However, much work still has to be done to elucidate the intrathymic role of these neuropeptides.

LeptinLeptin is expressed in the thymus and functions via the leptin receptor75. The db/db mouse line, which lacks the leptin receptor, develops type 2 diabetes melli-tus and obesity. In our own research, we have shown that db/db mice also undergo a precocious thymic involu-tion, with severe loss of thymocytes and accumulation of adipocytes within the organ76.

Expression of the leptin receptor in the thymus seems to be restricted to the microenvironmental cells and its activation by leptin protects against loss of lymphoid and TEC populations during stress-induced acute atrophy of the thymus77. However, no effect on thymopoiesis is observed with the administration of leptin to healthy mice78. Accordingly, intrathymic leptin mRNA is selec-tively increased in microenvironmental cells in the young rats from protein-deprived dams, which in turn protects thymocytes from apoptosis75. The function of both leptin and ghrelin support thymopoiesis. In addi-tion to changing the TCR repertoire, both hormones partially reverse age-associated thymic involution, albeit by distinct mechanisms56,79.

Thyroid hormoneSeveral lines of evidence suggest that circuitry associ-ated with thyroid hormone can modulate the function of the thymus. For instance, patients with hyperthyroid-ism have increased numbers of thymocytes, which leads to thymic hyperplasia in these individuals80. Consistent with this finding, mice exogenously injected with T3 exhibit an increase in the volume of the thymus, its cel-lularity and the cycling of thymocytes81. Moreover, sys-temic treatment or intrathymic injection of T3 enhances thymocyte adhesion and migration towards extracellular matrix mol ecules82,83. Such biological effects occur via activation of T3 nuclear receptors, which are expressed in both developing thymocytes and TECs84.

Table 1 | Intrathymic expression of hormones and correspondent receptors

Hormone Site of production Receptor expression Study

Thymocytes TECs Thymocytes TECs

Hypothalamus/neurohypophysis

TRH + ND + ND 88,90

Progonadoliberin-1 + ND + ND 99,100

CRH + ND ND ND 121

AVP ND + + ND 12,72,73,164

OT ND + + ND 12,72,73,164

Adenohypophysis

GH + + + + 41–44

TSH ND + + ND 86,87

Prolactin + + + + 44,59–61

ACTH ND + + + 118–120,165

Other organs

Ghrelin + + + + 54,56,148

Leptin ND + + + 75,77,166

T3

ND ND + + 84,167

Glucocorticoids + + + + 106,107,111, 112,116

Androgens ND ND + + 93,94

Estrogen ND ND + + 92

+ indicates that the hormone or its receptor has been detected at these sites. Abbreviations: ACTH, adrenocorticotropic hormone; AVP, arginine vasopressin; CRH, corticotropin- releasing hormone; GH, growth hormone; ND, not determined; OT, oxytocin; T

3, triiodothyronine; TEC, thymic epithelial cell; TRH, thyrotropin-releasing hormone.

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Although the intrathymic production of thyroid hor-mone has not been reported, immunocytochemical data indicate that TSH can be produced by TECs, as detected by immunohistochemistry with β-TSH anti bodies in the subcapsular and cortical thymic zones85. Moreover, TSHR (which encodes thyrotropin receptor, the recep-tor for TSH) is differentially expressed during human T-cell development in the thymus, and mice lacking functional thyrotropin receptor expression have lower numbers of DP and SP thymocytes than wild-type mice, which suggests that TSH functions as a growth factor for developing T cells86. Accordingly, deregulation of TSHR-mediated regulatory activity of gene expression, through the inhibition of its transcriptional repressor promyelo-cytic leukemia zinc finger protein in the thymus, triggers thyroid auto immunity due to the escape of TSHR-reactive T cells from negative selection87. Additionally, TRH, which encodes prothyrotropin-releasing hormone, is also transcribed in the thymus of the rat88. Given the local production of prothyrotropin-releasing hormone, the intrathymic expression of the thyrotropin receptor and the fact that this neuropeptide is able to enhance thymocyte prolif eration89,90, an autocrine/paracrine circuit mediated by thyrotropin receptor might control the thymus physiol ogy. However, whether a complete thyrotropin-releasing hormone–TSH–T3/T4 cascade occurs in the thymus remains to be defined.

Sex hormonesReceptors for androgens and estrogens have been found in both thymocytes and microenvironmental cells8,91,92. Developing androgen receptors are mainly found in the DN and CD8+ SP subsets93,94. Estrogen receptor signalling is required for the normal development of the thymus in mice95,96. This hormone also prevents the development of human thymoma through the inhib-ition of TEC proliferation, as ascertained by the addition of estrogen and anti-estrogens to primary cultures of human thymoma epithelial cells97. Although both estro-gen and androgens have inhibitory effects on thymus growth, in ovari ectomized mice the increase in numbers

of peripheral T cells is not associated with enhanced thymopoiesis, as observed after orchidectomy98. In this study, the effect seems to be due to an expansion of the numbers of pre-existing cells in the periphery98.

Although production of sex steroids has not been seen in the thymus, progonadoliberin-1 (also known as luteinizing hormone-releasing hormone), which stimulates the hypothalamus–pituitary–gonad axis, is known to be expressed by thymocytes in the thymus of rats99. In rats, progonadoliberin-1 can also stimulate the proliferation of these cells through direct action on progonadoliberin-1-specific receptors100.

GlucocorticoidsImmature DP thymocytes are major targets of gluco-corticoid-associated immunosuppression in the thy-mus, and this population of cells undergoes high levels of apoptosis and decreased proliferation upon gluco-corticoid stimulation101,102. However, the distinct effects of glucocorticoids on thymocytes seem to be dose dependent. Although high glucocorticoid levels are required for the induction of apoptosis in these cells, the exposure of thymo cytes to low glucocorticoid levels rescues these cells from TCR-mediated apoptosis103,104. Moreover, a local circuitry mediated by TEC-produced glucocorticoid has been suggested as the main medi ator of a glucocorticoid-positive role in thymocyte selec-tion39, decreasing the affinity with which TCR binds to MHC-presented self-ligands and rescuing thymo-cyte cells from a negative selection route. Although the absence of gluco corticoid receptor signalling has no impact on thymo cyte development105, the deletion of glucocorti coid receptors before selection leads to a decreased thymus size. This effect is associated with increased antigen-specific negative selection of DP thymo cytes and alterations in the TCR repertoire of polyclonal T cells103.

Glucocorticoid receptors are expressed in both the cytoplasm and nucleus of thymocytes106,107. On bind-ing, glucocorticoid–glucocorticoid receptors com-plexes translocate to the cell nucleus to modulate the

Table 2 | Pleiotropic effects of hormones on the thymus

Parameters Hormones Study

AVP OT GH Ghrelin Prolactin Leptin T3 GC Androgens

Size of the organ ND ND ↑ ↑ ↑ ↑ ↑ ↓ ↓ 81,127,168–171

Cellularity ND ND ↑ ↑ ↑ ↑ ↑ ↑ or ↓ ↓ 45,60,78,172,81,140

Thymocyte proliferation ND ND ↑ ↑ ↑ ↑ ↑ ↓ ↓ 77,79,140,173,174

Thymocyte differentiation ↑ ↔ ↑ ↑ ↑ ↑ ↑ ↑ or ↓ ↓ 45,51,52,82,171,175

Thymocyte death ↔ ↓ ↔ ND ↓ ↓ ↑ ↑ or ↓ ↓ 70,72,74,77,176–178

Intrathymic T-cell repertoire ND ND ↑ ↑ ↓ ↑ ND ↑ ↑ 39,56,179,180

TEC proliferation ND ND ↑ ↑ ↑ ↑ ND ↓ ↓ 36,61,181,182

TEC death ND ND ND ND ND ↓ ND ↑ ND 77,183

Thymic hormone production ND ND ↑ ND ↑ ND ND ↑ ↑ 170,184

↑, increase; ↓, decrease; ↔, no effect. Abbreviations: AVP, arginine vasopressin; GC, glucocorticoid; GH, growth hormone; ND, not determined; OT, oxytocin; TEC, thymic epithelial cell.

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expression of target genes (FIG. 4)108–110. Correlating with the increased sensitivity to the effects of gluco-corticoids, the density of glucocorticoid receptors is increased in immature thymocytes in the human thymus compared with mature thymocytes111.

In our own research, we have demonstrated that increased exposure to circulating glucocorticoid decreases glucocorticoid receptor-α expression in the DP cell subset in mice60. Glucocorticoid receptors have also been detected in TEC cultures112, and the β isoform of this receptor, which has been reported to have a dom-inant negative effect on glucocorticoid α-induced trans-activation of glucocorticoid response element-driven promoters113, was detected in situ in medullary TECs114.

In addition to expressing glucocorticoid receptors, both TECs and developing thymocytes express all the enzymes and cofactors required for the production of glucocorticoids115. Corticosterone is produced by TECs, whereas the synthesis of glucocorticoid by thy-mocytes was also elegantly demonstrated in a cell line transfected with glucocorticoid receptors and coincu-bated with thymocytes116. Specifically, DP cells seem to be the main thymocyte subset that produces gluco-corticoids117. Thymocyte-derived glucocorticoids have an anti- proliferative effect on the cell line and induced apoptosis in thymocytes117.

POMC (the gene that encodes for proopiomelano-cortin, which is cleaved into adrencorticotropic hor-mone) also seems to be constitutively expressed in TECs and TDCs118,119. The adrencorticotropic hor-mone receptor, melanocortin receptor subtype 2, is expressed on TECs and its activation regulates thymo-cyte expansion when the systemic concentration of glucocorticoid is low120. The intrathymic production of corticotropin-releasing factor by thymocytes has also been reported121. Taken together, these findings suggest that a circuitry, similar to that seen in the hypothalamus– pituitary–adrenal axis, might also occur within the thymus, but this system needs to be investigated further.

Infection and T‑cell developmentAtrophy of the thymus is a common feature in acute infections of viruses, bacteria, parasites or fungi122. Such atrophy is frequently associated with hypothalamus–pituitary–adrenal dysfunction, and can be exem-plified by the changes seen in patients with Chagas disease, which is caused by the protozoan parasite Trypanosoma cruzi and is a major public health issue in Latin America. We have previously shown that the atrophy seen in mice who have acute T. cruzi infection is characterized by a loss of DP thymocytes expressing

GH

JAK2

P

PP

PSTAT5

CDK4

CDK2

Controla b cGH

*

GH

TEC

num

bers

(×10

5 )

Control

Treatment

4

3

5

2

1

0

STAT5

JAK2

STAT5STAT5

STAT5

CRE

Gene expressionc-MYC, CDK

growth factors,cytokines

Cytoplasm

Nucleus

PPSTAT5STAT5

Nature Reviews | EndocrinologyFigure 3 | GH signalling in TECs stimulates proliferation of T cells. a | GH binding to its receptor recruits and activates the receptor-associated JAK2 that in turn phosphorylates tyrosine residues within itself and the GH receptor. These tyrosines form binding sites for a number of signalling proteins, including members of the STAT family. Among the known signalling molecules for GH, STAT5 proteins have a particularly prominent role in the regulation of gene transcription. In the nucleus, phosphorylated STAT5 binds to the promoters of target genes, such as the CRE. b | A mouse TEC line treated with GH has increased expression of JAK2, STAT5, CDK2 and CDK4 (as determined by immunohistochem-istry). c | The overall numbers of TECs are also increased when treated with GH. Abbreviations: CDK, cyclin-dependent kinase; CRE, cAMP response element; GH, growth hormone; JAK2, Janus kinase 2; P, phosphorylated; STAT5, signal transducers and activators of transcription 5; TEC, thymus epithelial cell. Panel c modified with permission from Wiley © Savino, W. et al. Scand. J. Immunol. 55, 442–452 (2002)138.

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low levels of TCR, together with an abnormal release of immature thymocytes60,123,124. Some of these thymocytes have TCR Vβ families, which under normal conditions should have undergone apoptosis, but persist and might, therefore, lead to an autoimmune reaction125.

The T. cruzi-induced progressive atrophy of the thymus was paralleled by increased circulating levels of glucocorticoids126 and could be prevented in mice pre-viously adrenalectomized and treated with the gluco-corticoid receptor antagonist, RU486127. Interestingly, we also found decreased levels of corticoliberin in the hypothalamus of T. cruzi-infected mice, with no sig-nificant changes in the circulating amounts of adren-ocorticotropic hormone, but with high levels of IL-6, a cytokine known to function directly on adrenal cells to stimulate corticosterone release128,129. Moreover, levels of GH and prolactin were diminished in the pituitary gland of T. cruzi-infected mice and in vitro infection with the parasite of the rat pituitary tumour cell line, GH3, as determined using immunohistochemistry130. Prolactin has emerged as another stress-adaptation molecule with altered production during T. cruzi infection. Reversed kinetic changes have been found in the serum levels of glucocorticoids and prolactin in mice undergoing experimental acute Chagas disease60. This result suggests that the immunosuppression that appears after T. cruzi infection is partially related to a stress hormone imbalance (FIG. 4a).

Increased serum levels of glucocorticoid was accom-panied by a decrease in intrathymic levels of cortico-sterone during acute T. cruzi infection, which indicates that the control of intrathymic glucocorticoid produc-tion is independent of systemic glucocorticoid levels60. DP thymocytes from mice infected with T. cruzi also had reduced levels of glucocorticoid receptor mRNA, in addition to elevated expression of PRLR60. This finding suggests that prolactin counteracts the effect of gluco-corticoid by directly affecting gluco corticoid receptor signalling in DP cells (FIG. 4b). Accordingly, signalling generated by prolactin receptor, which is mediated by the STAT5 pathway, abro gates glucocorticoid-induced apoptosis in T cells131. Consequently, re-establishing systemic prolactin levels by treatment with metyrapone (which stimulates synthesis of adrenocorticotropic hor-mone) can prevent thymic atrophy by decreasing both DP cell apoptosis and the numbers of DP cells in the periphery of the immune system60. This finding indi-cates that prolactin-mediated protection of the thymus also influences the abnormal export of these immature potentially autoreactive T cells60.

Hormone therapyThe thymus undergoes a physiological age-dependent involution with changes in both microenvironment and lymphoid compartments that usually result in the loss of T-cell export to the periphery of the immune system34,132.

c

Thymus

Adrenal

ACTH

PituitaryTrypanosoma cruzi

infection

ba

↑ GC

↓ PRL

GCGene

expressionPro-apoptotic

genes

Increased apoptosis

GC

GC

GCGC

GC

GRE

JAK2P

PSTAT5

PSTAT5STAT5

STAT5

P

Partial blockade of apoptosis

PRLPRLGC

GC

GCGC

GC

GCGene

expressionPro-apoptotic

genesGRE

PPSTAT5

STAT5↑ PRL↓ GC

Nature Reviews | EndocrinologyFigure 4 | Trypanosoma cruzi infection and thymus homeostasis. a | T. cruzi infection results in an increased systemic production of glucocorticoids by the adrenal gland without altering levels of adrenocorticotropic hormone. At the same time, the infection decreases PRL synthesis and/or release by the pituitary. T. cruzi infection also decreases the intrathymic contents of glucocorticoids and increases levels of locally produced PRL. b | Immature DP thymocytes sensitive to T. cruzi infection-induced apoptosis have increased levels of GR (blue rectangle). Upon GC binding, the GR complex translocates to the nucleus where it drives the transcription of pro-apoptotic proteins from the GRE. c | Increased PRL-mediated STAT5 signalling (which is secondary to exogenous prolactin administration) has a protective effect during T. cruzi infection by binding to the GR complex and inhibiting the pro-apoptotic effects of GC. Abbreviations: ACTH, adrenocorticotropic hormone; DP, double positive; GC, glucocorticoid; GR, glucocorticoid receptor; GRE, glucocorticoid response element; JAK2, Janus kinase 2; P, phosphorus; PRL, prolactin; STAT5, signal transducers and activators of transcription 5.

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Although the overall numbers of T cells are not dimin-ished in the periphery of individuals as they age, naive T cells are replaced by memory T cells in both humans and mice133. Furthermore, the ageing process results in suppression of T-cell proliferation, cytokine production and CD8-mediated cytotoxicity, which contributes to a reduced response of T cells134.

An accelerated involution of the organ can be seen in pathological situations, such as malnutrition, and acute infections such as those caused by T. cruzi and Paracoccidioides brasiliensis, as well as some immuno-deficiency disorders such as HIV infection135,136. Accordingly, replenishing the thymus has been pursued as a potential t herapeutic strategy to prevent involution of the organ.

Age‑dependent thymus involutionThe serum concentrations of both GH and IGF-1 decline during ageing 137. GH increases TEC pro-liferation in vitro (FIG. 3b) and synergizes with anti-CD3 in its stimulatory effect on thymocyte pro-liferation138. Accordingly, GH is a potential adjuvant therapeutic agent to revert age-dependent thymic involution. Positive effects on the growth of the thy-mus in 24-month-old rats implanted with cells from a pituitary tumour producing both GH and prolac-tin have been reported139. Conversely, GH receptor knockout mice have a severe precocious decrease of thymulin production, indicating a functional defect of the thymic epithelial network140. Although studies on thymus function have not been reported in chil-dren with typical Laron syndrome (who have muta-tions in the gene that encodes GH receptor), they do exhibit major immune dysfunctions141,142. Interestingly, in mutations in STAT5b (which encodes a component of a GH signalling pathway), growth defects correlates with immunodeficiency141,142.

GH has the potential to improve thymic function, enhance bone marrow engraftment and stimulate haematopoiesis in immunosuppressed and aged ani-mals143,144. Moreover, in ageing mice, GH treatment enhanced the diversity of the peripheral T-cell reper-toire (as determined by PCR analysis of CDR3 length for several TCR Vβ genes)45. In addition to these find-ings in mice45,52,145, GH administration in adult humans who have GH deficiency enables the recovery of the numbers of thymic emigrant cells in the periphery46. These results clearly indicate that GH is important for the maintenance of T-cell output and thymocyte pro-liferation and that GH might therefore be useful for hormone replacement therapy46.

Many of the effects of GH administration are medi-ated by IGF-1. Indeed, administration of IGF-1 in vivo can partially reverse the age-associated mouse thymic involution and enhance thymopoiesis146. Furthermore, in mice lacking the IGF-1 receptor on thymocytes and T cells, development proceeds normally upon IGF-1 treatment, which seems to be dependent on an expansion in the numbers of TECs and their capac-ity to regulating the entrance of T-cell precursors into the thymus147.

However, treating ageing rodents with either GH or IGF-1 did not restore thymus cellularity to the levels seen in healthy young mice146. As the combined admin-istration of IGF-1 and young bone marrow cells resulted in a higher cellularity of thymus in these mice than in animals treated with GH or IGF-1, or bone marrow transplantation alone, ageing-related additional defects in the bone marrow might limit the magnitude of the rejuvenating effects of these hormones during ageing.

The expression of ghrelin and its receptor is also decreased in ageing mice56 and deletion of Ghrl accel-erates thymic involution, fibroadipogenetic trans-formation and adipogenesis in the mouse thymus148. Importantly, re-establishing the presence of ghrelin in the serum partially reverses the thymic involution pro-cess, increases the numbers of thymic emigrants and improves TCR diversity of peripheral T cells in ageing mice in a mechanism independent of IGF-1 induc-tion56. However, further studies are needed to elucidate if the disruption of a ghrelin–GH–IGF-1 axis underlies the effects of ageing on the thymus.

Treating 14-month-old mice with leptin can also lead to the recovery of thymopoiesis, which is charac-terized by an increase in thymus size and weight, the number of thymocytes, TECs and thymic emigrants56. In addition, during states of malnutrition, the balance between the levels of leptin and glucocorticoid is dis-rupted. This situation leads to a decrease in levels of leptin and consequent enhancement of glucocorticoid- mediated thymo cyte apoptosis with atrophy of the thy-mus; exogenous administration of leptin might reverse these effects149.

Atrophy of the thymus accelerates at puberty95, which suggests that increasing levels of sex steroids leads to this effect. Accordingly, exo genous administration of sex steroids, such as dihydro testosterone and estradiol, in adult mice causes a collapse of thymo poiesis that is associated with increased apoptosis of cortical thymo-cytes150. In addition, ablation of the production of sex steroids by surgical removal of the gonads or chemi-cal blockage (by interfering with the hypothalamus- derived progonadoliberin-1) can rejuvenate the thymus in rodents94,151,152.

Progonadoliberin-1 signalling depends on the activation of its receptor, which is a member of the G protein-coupled receptor family. The continuous exposure to the cognate ligand leads to downregula-tion of this receptor and consequently a decrease in the release of sex hormones by the gonads153. Studies conducted in rat thymocytes revealed a decrease in binding sites for progonadoliberin- 1 with age; the abil-ity of progonadoliberin-1 to modulate thymus function indicates that progonadoliberin-1 action has a direct effect on this organ100. Similar to the effect of testoster-one removal by castration, the administration of pro-gonadoliberin-1 agonists restores thymus weight and increases progonadoliberin-1 binding in the thymus of aged rats, resulting in a partial restoration of thymic structure and an increased thymocyte proliferation100,152. In addition to a decrease in thymocyte apoptosis (which is also high in ageing), a substantial increase in DN, DP

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cells and CD4+ SP subsets is observed in mice after cas-tration36. Such an effect seems to be partly related to the re-establishment of the epithelial compartment36.

Sex steroid ablation also increases bone marrow recovery in ageing animals152, although whether the thy-mus recruits precursor T cells in this scenario is unclear. Nevertheless, the interaction between Notch on develop-ing thymocytes and Dll4 on TECs can be modulated by sex hormones, as progonadoliberin-1 antagonists, which mimic sex steroid ablation, enhance thymopoiesis in aged and female mice by upregulation of Dll4 expression154.

Although ovarian estrogen ablation in ageing females also increases thymus cellularity, regeneration is more pronounced in men than in women, which proba-bly reflects the increased extragonadal production of estrogen by adipose tissue and liver seen after oophor-ectomy155,156. Despite the difference in the thymus physi-ology, progonadoliberin-1 analogues have been used in the treatment of both prostate and breast cancer that are hormonally sensitive157.

Hormone therapy in HIVHIV infection leads to severe atrophy of the thymus, with a substantial decrease in the total number of devel-oping thymocytes, with thymic microenvironmental cells also being affected135,158. Accordingly, the restora-tion of thymus function would be greatly beneficial for patients with HIV infection. GH and IGF-1 can promote the re-establishment of T-cell development in patients with HIV infection. Exogenously administered GH has a thymopoietic role in humans with HIV infection159. In this study, the investigators examined the thymus of patients with HIV-1 infection who received GH therapy, and found a marked increase in overall thymic mass and in the numbers of CD4+ T cells in the blood159.

In addition to the increased numbers of naive T cells in GH-treated patients who have HIV infection, many of the T cells are derived from expansion of the periph-eral naive CD4+ T-cell pool160. Whether these increased numbers of naive T cells were due to the increase in cells that have left the thymus was unclear. These cells might derive from the infiltration of mature peripheral T cells and from adipose tissue within the perivascular spaces of the thymic lobules161. However, with the use of highly aggressive anti-retroviral therapy and improved control of the inflammation in these patients, GH was found to enhance the number of mature thymocytes162, as meas-ured by both the frequency of T-cell receptor excision

circles (TRECs; which are small DNA circles present in T cells as a residue after TCR gene rearrangement) in circulating T cells, as well as the numbers of naive and total CD4+ T cells in the blood of these patients162. These findings provide compelling evidence that GH enhances T-cell production and export and, therefore, facilitates CD4+ T-cell recovery in individuals with HIV infection. A similar effect was found in another study, in which a daily treatment with low dose of recombinant human GH over 40 weeks stimulated thymopoiesis and the frequency of T-cell receptor excision circles in CD4+ T cells from patients with HIV infection undergoing highly aggressive anti-retroviral therapy163.

The improvement of function after removal of hor-mone therapy suggests that this treatment enables the entrance of thymocyte progenitors and developing thymocytes into the atrophied thymus, as well as TEC growth and T-cell output. However, despite these prom-ising results, studies with larger cohorts of patients are still required before GH therapy in patients with HIV infection enter into clinical practice.

ConclusionsHormonal control of thymus physiology is complex and involves both endocrine and paracrine signalling pathways. The molecular mechanisms underlying this control have been only partly determined, including the intrathymic expression of respective ligands and recep-tors. The intracellular signalling has also been partially defined, but much work remains. Genetic manipulation of animal models, including conditional knockouts for signalling pathways that target thymic-specific cell pro-moters, will also contribute to our deeper understand-ing of the molecular mechanisms that underpin the hormonal control of the thymus. Specifically, the func-tional rele vance of the various intrathymic hormonal circuitries will hopefully be defined.

In addition to physiological mechanisms, dysfunc-tion in the hormonal control of the thymus can be induced by endogenous or exogenous stimuli, trigger-ing or enhan cing disease. The consequences on the progression or regression of the disease in response to hormone therapy are largely unknown, except for some specific cases, such as HIV infection. However, investi-gators are beginning to apply hormonal manipulation of the thymus as an alternative therapeutic approach for specific acute infectious diseases as well as noninfectious immunodeficiency conditions, including ageing.

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AcknowledgementsWork in the authors’ laboratories was supported with grants from CNPq, Capes, Faperj and Fiocruz (Brazil), FOCEM (Mercosur countries) and CNRS (France). The conjoint work was developed in the framework of the Fiocruz–CNRS International Associated Laboratory of Immunology and Immunopathology.

Author contributionsAll authors researched data for the article, wrote, reviewed and edited the manuscript before submission. D.A.M.‑d.‑C., A.L. and W.S. made substantial contribution to discussion of the content.

Competing interests statementThe authors declare no competing interests.

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