A�

rchivum Immunologiae et Therapiae Experimentalis, 2001, 4�

9,� 231–237P�

L ISSN 0004-069X

Review

Immune-Endocrine Interactions of theHypothalamus-Pituitary-Thyroid Axis: Integration, Communication and Homeostasis

MATTHEW D. ARMSTRONG and JO�

HN R. KLEIN*M

�. D. Armstrong and J. R. Klein: HPT Hormones and Immunity

Department of Biological Science and the Mervin Bovaird Center for Studies in Molecular Bio� logy and Biotechnology, University ofT�

ulsa, Tulsa, OK, USA

Imagination is more important than knowledgeAlbert Einstein

Abstract. The immune and neuroendocrine systems are two essential physiological components of mammaliano� rganisms. Although each is primarily committed to a set of tasks involved, on the one hand, i

n the protection

from infection and disease, and on the other hand, in the regulation of metabolism and other physiologicala ctivities, there is also evidence indicating that active and dynamic collaborations exist between those systems int

�he execution of their designated functions. These interactions occur at many stages of embryonic and neonatal

d�evelopment, and they are a continual part of the normal homeostatic balance needed to maint

�ain health. The

p resent review discusses various historical and contemporary perspectives of immune-endo� crine interactionsi

nvolving the hypothalamus-pituitary-thyroid axis, and offers a hypothesis of how this aspect of the neuroendo-c� rine system participates directly in the immune response to antigenic challenge, infection and disease.

Key words: immune-endocrine; hormone; antigen-presenting cells; pituitary-thyroid; lymphocytes; immu� nity.

I�ntroduction

I�n its most elemental form, homeostasis can be

v� iewed as a state of equilibrium between various physi-o� logical and chemical processes. It is therefore reason-a ble, in fact essential, to assume that homeostasis at theo� rganismic level is a composite of its many interactivec� omponent parts – the totality of factors and events,w� hether structural, regulatory or effector in nature,

w� hich impinge upon the physiological operation of theo� rganism. In that context, the immune system and then� euroendocrine system are inextricably linked, thoughmany of the specific details of how this occurs have yett

�o be fully elucidated or remain incomplete. This is due,

a t least in part, to the sheer complexity of the immunea nd neuroendocrine systems individually and to the in-herent amplification of those complexities whenv� iewed as a whole.

Abbreviations used: APC – antigen-presenting cell, HPT – hypothalamus-pituitary-thyroid, TSH – thyroid-stimulating hormone (thy-r� otropin), IL – interleukin, IEL – intraepithelial lymphocyte, TCR – T cell receptor, TEC – thymus epithelial cell, TRH – thryrotropin-re-leasing hormone, TNF – tumor necrosis factor.

* Correspondence to: John R. Klein, Ph.D., University of Texas Health Science Center, Department of Basic Sciences, Dental Branch,6�516 John Freeman Ave., Houston, TX 77030, USA, e-mail:jklein@mail.db.uth.tmc.edu

Y�

et both systems share basic common properties inc� uriously similar ways. Consider, for example, thate� ach consists of highlyinteractive components that arew� idely dispersed throughout nearly all tissues of theo� rganism. Moreover, both are wonderfully modular,e� ach containing specialized parts designed to performspecific tasks, for example, the delivery of a given hor-mone to a particular hormone-responsive tissue in pre-c� isely the right amount at precisely the right time, ort

�he selective secretion of immunoregulatory cytokines

in a dedicated and controlled fashion.The immune and neuroendocrine systems are also

f�undamentally regulatory in nature. In the case of the

neuroendocrine system, this involves the control overn� early all aspects of growth and development, broad--spectrum metabolic regulation and the responsivenesst

�o stress, and the activation and balance of various hor-

mone-mediated processes, such as reproduction. In thec� ase of the immune system, this involves a complex seto� f internal regulatory elements (cells, molecules andm� ediators) used to adjust the duration and amplitude oft

�he immune response according to the type of threat

c� onfronting the organism. Moreover, a key feature ofb

�oth systems is a process of homeostatic regulatory

f�eedback that involves the shunting of signals used to

p erpetuate, accelerate or terminate a response asn� eeded.

Finally, and perhaps most importantly, both systemshave highlydeveloped sensory elements consisting ofc� ell-borne receptors selectively distributed on tissuest

�hroughout the organisms; these serve as exquisite

mechanisms for focusing biological activity along oper-a tionally defined pathways. Consequently, secretion ore� xpression of a functionally-relevant molecule by theneuroendocrine and immune systems has significanceo� nly in the context of those receptor-bearing cells,t

�hereby establishing a process of “ information” transferw� ith a remarkable degree of specificity. In fact, perhapsn� owhere else in the mammalian organism is this dis-t

�inction more handsomely drawn than within the im-

mune system, consisting of no less than two hundreda nd fifty cell surface molecules that govern a panopliao� f immunological activities and functions that regulatehematopoietic cell development and differentiation.

Immune-Endocrine Interactions Mediated byThyroid-Stimulating Hormone: Evidence for anI

�ntrinsic Autocrine/Paracrine Hormone Network

T�

hyrotropin (thyroid-stimulating hormone – TSH),a glycoprotein hormone produced by the anterior pitui-

t�ary and released into the blood upon induction by hy-

p othalamic-derived thyrotropin-releasing hormone(TRH), is composed of disulfide-linked α/β hetero-d

�imeric components17. The biological activity and spe-

c� ificity of TSH resides in the TSH β-chain molecule,w� hereas the α-chain is shared by other glycoproteinh

�ormones, including luteinizing hormone, follicle-sti-

mulating hormone and human chorionic gonadotro-p in17. Within the hypothalamus-pituitary-thyroid (HPT)a xis, TSH is involved in the regulation of the thyroidhormones T3

� (tri-iodothyroxine) and T4� (tetra-iodothy-

ronine) and, conversely, thyroid hormones exert bothp ositive and negative effects on the transcription of theTSH β-chain genes in the anterior pituitary, thus estab-l

ishing a hormone-mediated cycle of self-regulatoryc� ontrol. Although the activity of TSH is traditionallyregarded to be confined to the HPT axis, it is clear thatt

�he effects of TSH reach beyond the neuroendocrine

system.

TSH receptor expression within the immune system

Receptors for a wide range of neuropeptides andhormones are now known to be expressed on hemato-p oietic cells of mice, rats and humans (reviewed in ref.3

�2)

!.

Although relatively few studies have specifically exam-i

ned TSH receptor (TSHr) expression, there is, nonethe-

less, convincing evidence linking the presence of TSHrt

�o specific cells of the mammalian immune system. An

e� arly study, using radiolabeled TSH binding assaysw� ith peripheral blood leukocytes enriched by densityg" radient centrifugation, found TSH to preferentiallyb

�ind to phagocytic cells, in particular monocytes and

p olymorphonuclear leukocytes4�. These findings have

b�een confirmed and extended in studies of phenotypi-

c� ally-defined human peripheral blood leukocytes,w� hich demonstrated high level TSH binding to Leu-M3+#

monocytic/macrophage cells, as well as to the macro-p hage cell line U9375

$. Similarly, studies from our la-

b�oratory indicate that ~30–50% of CD11b+# /

%CD11c+# ad-

herent cells from the spleen and lymph nodes are TSHr+#

c� ells (Fig. 1A). Taken together, those findings providea strong consensus for a process of TSH utilization byp rofessional antigen-presenting cells (APCs), in par-t

�icular dendritic cells and macrophages. Perhaps most

importantly, however, this locates TSH-responsive cellsa t the core of both the adaptive and innate immuneresponses, a potentially important fact given the centralr& ole of APCs in the overall scheme of immune activa-t

�ion and regulation. However, because APCs are known

t�o be phenotypically heterogeneous, additional analyses

o� f TSHr expression on murine cells defined by cell

232 M. D. Armstrong and J. R. Klein: HPT Hormones and Immunity

surface markers 33D1, DEC-205, CD8a, Sca-2, CD24a nd c-kit, which are to varying degrees expressed ond

�endritic cells and/or macrophages27, should help con-

siderably in defining TSH-responsive APCs.The extent to which the TSHr is expressed on lym-

p hoid cells is less clear. Using human peripheral bloodl

eukocytes and tonsillar lymphocytes defined by CD4,

C'

D5, CD8 or CD19 expression, little or no binding toresting T cells or B cells was observed5

$. Likewise,

h�uman T cells stimulated with the T cell mitogen phy-

t�ohemagglutinin5

$ or murine T cells stimulated with sta-

p hylococcal enterotoxin-A (SEA)11 remained unable tob

�ind TSH. In contrast to T cells, activated but not rest-

ing B cells showed an increased ability to bind TSH5$,11,

a finding in line with an earlier study using humanB

( cell lines18 and implying a functional role for TSH in

t�he generation of a humoral immune response shortlya fter the initial activating steps have occurred.

Studies in our laboratory using murine lymphocytesfind little or no TSH binding to resting splenic T cellso� r B cells. Interestingly, however, a subset ofC

'D45RBhi, CD69– lymph node T cells bearing

a phenotype of naïv� e non-activated cells, includingb

�oth CD4+8– and CD4–8+ cells, express high levels of

T�

SHr (Fig. 1B and C), suggesting that there are anat-o� mical differences in TSH utilization by peripherall

ymphoid cells. While the meaning of the difference in

TSHr expression between splenic and lymph nodeT cells in mice is at present not fully known, it mayhave relevance for understanding immune-endocrinei

nteractions within and between peripheral lymphoid

t�issues. Consider, for example, that the spleen serves

p rimarily as an immunological filter for the blood,

w� hereas lymph nodes are sites in which tissue-deriveda ntigens are imported and delivered to T cells andB cells by APCs. Furthermore, these immunological in-t

�eractions in lymph nodes are most critical during the

g" eneration of a primary immune response leading tot

�he activation of naïv� e T cells, and are of less import-

a nce for the re-activation of effector or memory cells2)

6.In that context, studies using TSHr-defective animalssuch as C.RFTSHrh

*yt/hyt, mice may help considerably for

e� lucidating the impact of TSH on APC-mediated re-sponses during primary versus secondary immune chal-lenge.

T�

wo other hematopoietic cell populations in micehave recently been demonstrated to express TSHr. In-t

�estinal intraepithelial lymphocytes (IEL), a lymphoid

c� ell population consisting of T cells and a small butsignificant set of resident dendritic cells and macro-p hages, express surface TSHr as predicted from bind-i

ng studies and based on expression of TSHr gene tran-

scripts29. In this system, TSH has been shown tof

�unctionally influence the differentiation and/or the re-

d�istribution of IEL subsets within the intestinal epithe-

lium, as discussed in detail below. Similarly, based ong" ene expression, the TSHr was found to be expressedo� n hematopoietic cells of the bone marrow, though therelationship of specific TSHr+ stem cell subsets to ma-t

�ure leukocytes has not been determined3

�3.

Extra-pituitary production of TSH

T�

he awareness that cells of the immune systemu� tilize TSH prompts many questions, not the least ofw� hich is the source of TSH that is used by the immune

F+

ig. 1. Flow cytometric analyses of TSHr expression on purified murine CD11b splenic adherent cells (A), and whole lymph nodelymphocytes stained for CD4 expression (B)

,, and CD8 expression (C)

,

M. D. Armstrong and J. R. Klein: HPT Hormones and Immunity 233

system. Clearly, blood-borne TSH could serve in thisc� apacity. In that case, however, serum-derived TSH le-v� els would be largely dictated by the needs of the thy-r& oid rather than the immune system. Thus, the possi-b

�ility exists that extra-pituitary TSH is produced by

c� ells of the immune system itself. First evidence for thisw� as provided in experiments from SM

-ITH and col-

leagues23. Using density-gradient purified humanmononuclear cells, up to 50% of SEA-stimulated cellsc� ontained intracellular TSH that was immunologicallyindistinguishable from pituitary-derived TSH. TSH alsohas been shown to be produced by human T cell linesstimulated with SEA or TRH10. Using purified popula-t

�ions of murine splenic mononuclear cells defined by

f�low cytometry with markers specific for APCs, T cells

a nd B cells, we have found TSH-producing cells toreside among APCs, particularly dendritic cells, basedo� n intracellular staining with anti-TSHβ-specifica ntisera, and TSHβ secretion detected by enzyme-lin-ked immunoassays (EIA). Moreover, the activity ofT

�SHβ increased after dendritic cell activation upon

stimulation with anti-CD40 antibody in the presence ofIL-4, whereas murine T cells and B cells did not pro-d

�uce significant amounts of TSH regardless of their

state of activation (BA.

GRIACIK and KL/

EIN, unpublished).

Involvement of HPT hormones in immunes0 ystem function

Effects within the peripheral immune system. A rolef

�or TSH in antibody synthesis by B cells has been dem-

o� nstrated in several laboratories5$, 11, 15, 16. Using human

a nd murine lymphocytes or cell lines, 2–7-fold in-c� reases in immunoglobulin production have been re-p orted following in vitro co-culture of mitogen-acti-v� ated B cells with TSH. Similar positive effects oni

mmunoglobulin production have been noted in TRH--supplemented spleen cell cultures, in which there wasa concomitant release of TSH16. Although the cellularsource of TSH in those cultures was not determined,t

�he presence of TRH receptors on lymphoid cells has

b�een inferred from studies demonstrating TRH receptor

g" ene transcripts in rat and human cells2)

0, further sug-g" esting an intrinsic TRH→TSH pathway leading toa TSH-mediated intracellular signal. Moreover, be-c� ause TSH stimulation of B cells did not result in en-hanced B cell proliferation, the effect of TSH on anti-b

�ody production could not be attributed to an increase

in the numbers of B cells. Using the T cell-independenta ntigen, Brucella abortus-trinitrophenol (BA-TNP), thec� ostimulatory effects of TSH were augmented by mac-rophages and, curiously, were found to be strictly de-

p endent upon T cells15. Although at first glance the latterfinding seems difficult to reconcile for a T cell-inde-p endent antigen, it rather makes a strong case for thel

ikelihood that TSH is acting not on B cells, but that itis directed to accessory cells and possibly T cells,a scenario consistent with the notion of wide-spreadT

�SHr expression among APCs as discussed earlier.

Effects on the intestinal immune system. The intes-t

�inal mucosa constitutes an important host barrier to the

e� ntry and dissemination of foreign antigen. It is, thus,not surprising that the intestinal immune system hasd

�eveloped mechanisms of immunological protection

t�hat differ from those found in lymphoid tissues else-

w� here in the animal. Studies over the past two decadesr& eveal a remarkable level of phenotypic complexity ofi

ntestinal IELs, including several cell populations that

a re unique to the intestine. In mice, murine IELs area lmost exclusively of CD8+ T cells comprised of eitherT

�CRαβ or TCRγδ1 cells in roughly equal proportions14.

Moreover, ~75–80% of the IELs utilize a CD8αα ho-m� odimer rather than the CD8αβ heterodimer found onm� ost other peripheral T cells9

2,21. That feature has been

hypothesized to discriminate IELs along developmentallineages such that CD8αα IELs are considered to bee� xtrathymic T cells that have matured locally within theintestine, whereas CD8αβ IEL are believed to be ma-t

�ure thymus-derived T cells recruited into the gut fromt

�he periphery.

The distinction between CD8 expression and IELd

�evelopment becomes more dubious, however, in the

l ight of studies indicating that HPT hormone can in-

fluence the phenotypic composition of cells in the gute� pithelium. Mice thymectomized as neonates andt

�reated with TRH or TSH for three weeks beginning at

six weeks of age were found to have increases in thenumbers and proportions of CD8αβ IELs29,30, i.e. theI

�EL population generally considered to be “ thymus-de-

p endent” T cells (Fig. 2). Because the effect ofT

�RH/TSH treatment occurred in the absence of direct

immune augmentation and could not be accounted forb

�y increased proliferation of the small numbers of ex-

t�ant CD8αβ cells present in athymic mice, it was rea-

soned that the effect of hormone treatment was to com-p ensate for the disruption by thymectomy of ani

mmune-endocrine circuit that is needed for proper ma-

t�uration of the intestinal epithelium as a site for immu-nological development29,31.

Effects on bone marrow stem cells. The influence ofT

�SH also can be seen in the bone marrow. Bone mar-

row hematopoietic cells cultured in vitro with eitherp urified TSH or antibodies to the TSHr result in rapidb

�ut selective cytokine production as determined by EIA

234 M. D. Armstrong and J. R. Klein: HPT Hormones and Immunity

a nd cytokine gene transcription in RNase protectiona ssays3

�3. Thus, gene activation and/or cytokine produc-

t�ion for interleukin (IL)-6, tumor necrosis factor (TNF)-α,

T�

NF-β, lymphotoxin-β, interferon-β, and transformingg" rowth factor-β2, but not IL-1β, IL-2, IL-12, or inter-f

�eron-γ1 , were observed3

�3. Also of interest in those

studies was the finding that TSH stimulation of bonemarrow cells resulted in rapid phosphorylation of theJ

3AK2 protein kinase with concomitant increase in

c� AMP levels, implying that novel intracellular signal-ing events may be used in the course of TSH activation.

The Thymus-Thyroid Connection

Regulation of thymus function and peripheralimmunity by thyroid hormones

A role for the thyroid in the regulation of thymusa ctivity can be seen during many stages of developmenta nd aging. For example, although it is well known thatm� ice which are athymic during fetal and/or early neo-natal life undergo a wasting process characterized byl

oss of weight and a generalized failure to thrive, a pro-c� ess similar to wasting can be induced when pituitary--thyroid hormone activities are suppressed in neonatale� uthymic mice19. Although wasting likely reflects, toa large degree, an inability of the animal to mount ane� ffective T cell-mediated response to infection, the abilityt

�o prevent wasting through thyroid supplementation with-o� ut thymus intervention further underscores a basic rolefor the thyroid in the expression of immunity.

W4

hile the mode of action of thyroid hormones ont

�hymus activity is undoubtedly complex, potentially af-

fecting many cellular activities, some of this appears to

r& eflect the modulation of thymus-derived thymulin asseen by correlations between T3

� levels and circulatingt

�hymulin22. Those findings are supported by other

studies indicating that naturallyoccurring hypothyroidhuman infants, as well as mice treated experimentallyw� ith 6N-propyl-2-thiouracyl as an inhibitor of thyroidh

�ormone synthesis, have depressed thymulin levels2

)2.

Furthermore, although circulating thymulin levels dis-p lay age-dependent differences in humans, rangingf

�rom high levels by the second decade of life to low

levels by the 6th decade of life, hypothyroidism iny5 oung adults depresses thymulin to levels similar tot

�hose found in aged persons, while hyperthyroidism in

o� lder adults leads to elevated thymulin levels resem-b

�ling that of young adults8.

T�

hese observations, while tantalizing, by themselvesp rovide only indirect evidence of a thyroid→t

�hymus

regulatory event: one which may be secondary to a pro-c� ess of enhancement or suppression of metabolic acti-v� ities broadly controlled by thyroid hormones. To cir-c� umvent that problem, investigators have used culturedh

�uman or rat thymic epithelial cells (TECs) and have

measured secreted thymulin in the presence and ab-sence of thyroid hormone, in this case T3

� . Beginning3–5 days after culture, thymulin levels were significant-ly and continually elevated in T3

� -supplemented cul-t

�ures, implying a direct effect of thyroid hormone on

TECs66. Although those studies have not been extended

t�o other thymus-derived peptides and mediators pro-

d�uced by TECs, the potential for extensive immuno-

m� odulating effects exerted by thyroid hormones on in-t

�rathymic T cell development warrants further study.

A7

dditional direct evidence for thyroid regulation ofimmunity comes from experiments using the autoim-mune gastritis model in day 3 neonatally-thymec-t

�omized mice. In that system, organ-specific autoim-

m� une diseases of the stomach and reproductive tissues,w� ith onset in young adult mice between 6 to 9 weekso� f age, can be elicited following neonatal thymectomyb

�etween days 1 and 3 post-birth2

)4. Disease is mediated

p rimarily by CD4+# T cells and autoantibodies, and ex-p ression of disease is closely linked to whether or nott

�he thymus is present during a critical phase of immu-

nological (and neuroendocrine) maturation24. Hence,m� ice lacking a thymus throughout fetal life, i.e. con-g" enitally athymic nude mice, rarely develop those auto-immunities; mice thymectomized on or after day 5 post--birth are similarly unaffected. Because T cells arep roduced in mice beginning at the time of birth, it hasb

�een speculated that thymus removal during that period

l eads to perturbations in regulatory T cell subsets that arec� ritical for maintaining peripheral self tolerance3

�.

Fig. 2. Percent of CD8α8 α and CD8α8 β intestinal IELs from ninew9 eek old neonatally-thymectomized mice without hormone treat-ment, and from neonatally-thymectomized mice treated with TRHo� r TSH for three weeks beginning at six weeks of age. Notet:he increase in numbers of CD8α8 β+ IELs following TRH or TSHt:reatment

M. D. Armstrong and J. R. Klein: HPT Hormones and Immunity 235

W4

ith that model, it was demonstrated that day 1–3neonatally-thymectomized mice treated with T4

� justp rior to the time of disease onset had lower incidencesa nd severity of gastritis compared with untreated miceo� r with mice treated with TSH or TRH2

)8. This is to say

t�hat, exposure to exogenous T4 as the autoimmune re-

sponse is developing appears to compensate for an in-herent thymus-associated immune deficiency resultingfrom thymectomy during the immediate post-birth period.

Inflammatory cytokines and thyroid function

I�mmune system cytokines, in particular inflamma-

t�ory cytokines such as IL-1β, IL-6, and TNF-α, have

p leiotropic effects on thyroid cell growth and functiona s measured by modulation in thyroglobulin productiona nd cAMP levels in primary thyroid cells and cell linessuch as FRTL-5 cells. An early study by DU

;BUIS et. al.7

<

r& eported a precipitous decline in serum TSH levelsw� ithin 5 h of a single injection of recombinant humanI

�L-1β. Recovery to normal TSH levels occurred within

12–24 h, but was followed by a concomitant decreasein total serum T4

� and an increase in free T4� 2

)8. Similar

findings have been observed in rats undergoing con-t

�inuous infusion of IL-1 and IL-6, as well as with TNF-α

e� xposure, even in the face of TSH supplementation12,suggesting that in those situations adjustments in thy-roid activity may not be mediated through the conven-t

�ional hypothalamus-pituitary feedback loop, but may

b�e regulated from within the immune system itself.

P=

ossibly the most interesting aspect of the abovestudies, however, is that all the cytokines in questiona re produced by professional APCs and all have proper-t

�ies tied to the regulation of inflammatory responses.

Still other studies report gene transcripts for IL-1α, IL-6,IL-8, IL-12, IL-13 and IL-15 in thyroid follicular cellsf

�rom patients with thyroid dysfunction and in normal

t�hyroid tissues (reviewed in ref. 1).

A Model for TSH-Mediated Immune-EndocrineInteractions in Health and Disease

The information presented here demonstrates thed

�ynamic manner by which the immune system and the

e� ndocrine system interact and communicate, and howt

�hose physiological entities function to regulate each

o� ther. How, then, might these interactions have biologi-c� al significance in the broader scheme of immunity?Recall that professional APCs consist of cells that canp roduce and utilize TSH, though not necessarily by thesame subsets, thus establishing a TSH-driven response

system wholly contained within the immune system.W

4ith that, we envision a process whereby both the

a daptive and innate branches of immunity converget

�hrough the use of TSH, particularly in response toa strong antigenic challenge. Although TRH mightserve as an activating signal in this pathway, inductionb

�y antigens such as bacterial endotoxin is more feasible

from an immunological perspective. Rapid release ofTSH from cytoplasmic endosomes then would be avail-a ble for local use by appropriate APCs, T cells andB cells, thereby enhancing cytokine synthesis, T cella ctivity and antibody responses from B cells.

F>

urther amplification of the effects of these im-mune-endocrine interactions would be manifest ina number of ways. TSH-mediated enhancement of theA

7PC-derived cytokines, IL-1β and IL-6, would provide

a n additional level of protection to the host by inducinga febrile state upon direct stimulation of the hypothala-m� us13 and would suppress thyroid activity2

)5. This

w� ould be accompanied by a transient decline in serumt

�hyroid hormone levels during the days immediately

f�ollowing antigen exposure. Such changes in thyroid

hormone levels have been reported in mice followingsystemic antigen challenge (ref.2, and BAGRIACIK andK

?L

/EIN, unpublished), although the mechanism(s) which

a ccount for that are currently obscure.I

�mmune-endocrine changes of this type have many

features consistent with extant observations pertainingt

�o the natural immune response. For example, the ma-

laise frequently experienced during the early period fol-l

owing virus or bacterial infection may be due to a dropin thyroid hormone levels, forcing the host into a periodo� f inactivity. Yet, this could be deleterious to the hostif the biological activity of the immune response weresimultaneously compromised. Interestingly, however,w� e have observed that slightly lower levels of thyroidh

�ormones favor the production of IFN-γ1 , a Th1 cyto-

kine that is involved in early events leading to immunea ctivation and also has anti-viral and anti-bacterial ac-t

�ivities.

Finally, we predict that suppression of thyroid hor-mone activity is subsequently compensated for by den-d

�ritic cells or other TSH-producing APCs which mi-

g" rate to the thyroid, rather than by regulation fromp ituitary-derived TSH. In this pathway, therefore, TSHp lays a critical role at two levels, the first being withint

�he immune system itself as an endogenous mediator of

immune activity, the second being as a molecular sig-n� al used by the immune system to communicate witht

�he thyroid. Clearly, as is true for other types of im-

m� une-endocrine interactions, many aspects of this sys-t

�em remain to be explored empirically.

236 M. D. Armstrong and J. R. Klein: HPT Hormones and Immunity

R@

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Received in February 2000Accepted in April 2000

M. D. Armstrong and J. R. Klein: HPT Hormones and Immunity 237