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,
Departments of
*
Neurology and
Molecular Microbiology and Immunology, Oregon Health Sciences University, and
Department of Veterans Affairs, Neuroimmunology Research, Portland, OR 97201
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and more IL-10
than untreated cell lines. Clinical disease induced by the adoptive
transfer of androgen-selected T cell lines was less severe than disease
induced with untreated T cell lines. Furthermore, androgen treatment of
naive TCR transgenic T cells, during their first encounter with Ag,
resulted in a shift in the balance of Th1/Th2 cytokines. This phenotype
was maintained during subsequent stimulations in the absence of
androgen. These results suggest that androgen present in the lymphoid
microenvironment during the induction of an immune response can alter
the development of effector T cells and may play an important role in
governing gender differences in the immune response and susceptibility
to autoimmune disorders. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Experimental autoimmune encephalomyelitis (EAE) is an inflammatory
demyelinating disease of the central nervous system that is induced by
immunizing susceptible animal strains with myelin proteins or peptides
(6). EAE is a useful model that has provided considerable insights into
the pathogenesis of MS. The inflammatory CD4+ T cells that
mediate EAE secrete Th1 cytokines, including IL-2, IFN-,
lymphotoxin, and TNF (7, 8, 9). In contrast, Th2 cells secrete
IL-4, IL-5, IL-6, IL-10, IL-13, and TGF-ß, and are thought to
down-regulate EAE (10, 11). Skewing of the response toward Th1 or Th2
phenotype can be influenced by the quantity of Ag, the site of
immunization, the initial APCs that interact with naive T cells, and
cytokines (12, 13). Attention has focused primarily on the cytokines
produced by either the APC or lymphocytes. However, the role of steroid
sex hormones in controlling patterns of T cell lymphokines has been the
focus of several recent studies. Piccinni et al. demonstrated that
progesterone can favor the development of Th2 cells, and induces IL-4
mRNA in established Th1 cell lines (14). Estradiol was shown to enhance
IL-10 IFN- and regulate TNF secretion in a dose-dependent manner
(15). In addition, androgens have been shown to regulate cytokine
secretion (16). Treatment of experimental animals with androgen or
estrogen has been shown to alter Th differentiation and the clinical
course of EAE (17, 18, 19). The influence of sex hormones on the immune
response is further supported by evidence demonstrating sex hormone
receptors in immunocompetent cells (20, 21).
Although an immunomodulatory function for sex hormones is supported by experimental and clinical observations, the cellular targets of these hormones in the immune system have not been clearly defined. The results of this study demonstrate for the first time that androgens can regulate cytokine synthesis of encephalitogenic T cells in vitro and alter the clinical course of adoptively transferred EAE. These data are consistent with the hypothesis that gender differences in autoimmunity can be due to the direct actions of sex hormones on immunocompetent cells during the induction of the immune response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Age-matched (5-wk) male and female SJL/J mice were purchased
from The Jackson Laboratory (Bar Harbor, ME). Young adult (
8-wk-old)
SJL mice were used for all of the experiments mentioned in this study.
Transgenic mice bearing the functionally rearranged BV8S2 TCR gene on a
B10.PL background were kindly provided by Dr. Joan Goverman (University
of Washington, Seattle). The animals were bred and housed in the Animal
Resource Facility at the Portland Veterans Affairs Medical Center in
accordance with institutional guidelines.
Antigens
Mouse proteolipid protein (PLP) 139–151 (HCLGKWLGHPDKF) and N-acetylated myelin basic protein 1–11 (Ac-ASQKRPSQRSK) were synthesized using solid-phase chemistry on a Synergy 432A peptide synthesizer (Applied Biosystems, Foster City, CA), and purified before use.
Adoptive transfer of EAE with T cell lines
T cell lines were developed as previously described (22). Briefly, draining lymph node and spleen cells were recovered from the animals 10 days after immunization with PLP 139–151 and CFA. The T cells were selected by stimulation for 72 h with peptide, then allowed to expand in growth media containing IL-2 (25 U/ml) for 7–10 days. The specificity of the T cell lines was routinely monitored by proliferation assay, as described previously (22). The T cells were subsequently restimulated with autologous, irradiated APC and PLP 139–151 for 72 h before adoptive transfer. A quantity amounting to 5 x 106 T cell blasts was transferred i.p. into naive male or female SJL mice at either the first or second restimulation. The animals were monitored daily, for clinical signs as described in Ref. 22.
Cytokine detection by ELISA
PLP 139–151-specific T cell lines were suspended to 0.5 x
106 cells/ml and cocultured with 5 x 106
irradiated spleen cells as APC in stimulation media. Cell culture
supernatants were recovered at 72 h and frozen at -70°C until
needed for cytokine assay. Measurement of cytokines was performed by
ELISA developed in our laboratory using cytokine-specific capture and
detection Abs (PharMingen, San Diego, CA). Standard curves for each
assay were generated using recombinant mouse cytokines
(PharMingen), and the concentration of cytokines in the cell
supernatants was determined by extrapolation from the appropriate
standard curve. IFN- and TNF-
were chosen as representative Th1
cytokines, while IL-5 and IL-10 were measured as representative Th2
cytokines since the levels of IL-4 were low and irreproducible.
Hormone treatment and adoptive transfer
Spleen cells were harvested from male and female SJL mice 10 days after immunization with PLP 139–151 and stimulated as described above in the presence or absence of 10 nM testosterone. The cells were allowed to expand for 7 days in growth media containing 25 U/ml of IL-2, before restimulation with and without 10 nM testosterone. An aliquot of cells was used to measure Ag-specific proliferation, and an additional aliquot was used to analyze cytokine secretion. The remainder of the activated T cells were transferred into naive male and female SJL hosts (5 x 106 cells/mouse), and the animals were monitored daily for clinical score.
Androgen and estrogen receptor mRNA detection
Splenocytes were obtained from naive male and female SJL mice, then stained with FITC-labeled anti-CD4 or Mac-1-specific Abs (PharMingen), followed by an anti-FITC, paramagnetic microbead-labeled secondary Ab. The cells were then sorted on a Macs magnetic separation column (Miltenyi Biotec, Auburn, CA). Total cellular RNA was isolated from 5 x 105 CD4+ (95% pure) and Mac-1+ (96% pure) cells using a modified guanidinium thiocyanate-phenol-chloroform single extraction method (23). First strand cDNA was synthesized from total RNA using MLV reverse transcriptase (BRL, Bethesda, MD). Cell equivalent amounts of cDNA (approximately 10,000 cells) were used per PCR. Each sample was normalized by PCR amplification with control primers specific for mouse actin. The normalized amount of cDNA was added for each sample, then PCR amplified with specific oligonucleotide primers specific for androgen receptor (sense, 5'-TCT CAA GAG TTT GGA TGG CTC C-3'; antisense, 5'-GAG ATG ATC TCT GCC ATC ATT TC-3'); estrogen receptor (sense, 5'-GAG ACT GTC CAG TAA CGA GAA-3'; antisense, 5'-GGA CAA GGC AGG GCT ATT C-3'); and actin (sense, 5'-ATC TAC GAG GGC TAT GCT CTC C-3'; antisense, 5'-AAT CTC CTT CTG CAT CCT GTC AGC-3').
Statistical analysis
Mean cytokine levels were calculated from triplicate
measurements and compared using the Student’s t test. Mean
day of onset, disease score at peak, and mean cumulative disease index
(CDI) were also compared using the Student’s t test. The
incidence and mortality of disease were compared by 
2
analysis using the Yates correction (24).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The SJL mouse strain is highly susceptible to the adoptive
transfer of EAE and has an MHC background (H-2s) previously
shown to lack antisyngeneic HY responses (25). Furthermore, the
feasibility of intergender adoptive transfer for the study of gender
differences in EAE has recently been reported (26). Our initial
experiments were designed to verify differences in the ability of male
and female T cells to transfer EAE. T cell lines were derived from PLP
139–151-immunized male and female mice and transferred into naive
female recipients. The specificity of the T cell lines was confirmed
before the adoptive transfer of 5 x 106 T cell
blasts. No significant differences in the proliferation of male and
female T cell lines were measured (data not shown). Nevertheless,
animals receiving female T cell lines had a higher incidence of EAE, an
increased rate of mortality, and significantly more severe clinical
symptoms than animals receiving male T cell lines (Fig. 1
, A and B).
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Both male and female T cell lines were predominantly
CD4+, and no significant differences in the expression of
adhesion molecules (L-selectin, VLA-4, LFA-1), or activation markers
(OX40, CD69) were observed (data not shown). The possibility that
gender differences in T cell cytokine secretion were responsible for
differences in the clinical disease course was tested by measuring
cytokine levels in male and female T cell lines. Spleen cells were
removed from PLP 139–151-immunized male and female SJL mice and
stimulated in vitro for 72 h. The cells were then placed in
IL-2-containing growth media for 5–7 days before being restimulated.
Cytokine secretion by male and female T cell lines after restimulation
with PLP 139–151 in vitro was measured, and the results are presented
in Fig. 2. Although there were no
differences in Ag-specific proliferation between males and females
(data not shown), significant gender differences in cytokine production
were observed. Female T cell lines secreted more IFN- than IL-10,
indicative of a Th1 response, while male T cell lines made more IL-10
than IFN-, indicative of a Th2 response (Fig. 2). Gender differences
in cytokine secretion may be responsible for differences in the
severity of adoptively transferred EAE.
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We tested the hypothesis that sex hormones alter T cell function
by examining the effects of androgens on T cell proliferation, cytokine
secretion, and the ability of activated cells to transfer EAE. T cell
lines from PLP 139–151-immunized female SJL mice were selected by in
vitro stimulation with or without the androgen dihydrotestosterone
(DHT). Although no differences in the proliferation of DHT-treated and
control cell lines were observed (data not shown), T cell lines treated
with physiologic levels of DHT had a significantly lower IFN- to
IL-10 ratio (Fig. 3A). The
decreased IFN-:IL-10 ratio was due both to a reduction in IFN-
and an increase in IL-10 secretion by DHT-treated cells (Fig. 3B). PLP-specific T cell lines derived from female SJL mice
were also selected in the presence or absence of testosterone. Similar
to what was observed with DHT, physiologic levels of testosterone (10
nM) reduced IFN-, and enhanced IL-10 secretion (Fig. 4B), resulting in a
significant reduction in the IFN-:IL-10 ratio (Fig. 4A).
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, and had elevated levels of IL-5 and IL-10
(Table I). Testosterone treatment of
either control T cells (not previously treated with testosterone) or
testosterone-selected T cells significantly inhibited IFN-
secretion, but had no effect on TNF-, IL-5, or IL-10 production
(Table I).
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).
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Our data are consistent with the notion that Th cells are
sensitive to testosterone-mediated regulation. It is, however, not
clear that Th cells express sex hormone receptors. To elucidate this
issue, we purified CD4+ T cells and Mac-1+
macrophages from the spleens of normal SJL mice and examined these
cells for the expression of sex hormone receptor mRNA. Androgen and
estrogen receptor mRNA was detected in both CD4+ T cells
and Mac-1+ macrophages (Fig. 5). These results indicate that both
CD4+ and Mac-1+ cells can be targets for the
actions of sex hormones.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), and more Th2 (IL-10)
cytokines. Furthermore, androgen treatment of naive TCR transgenic T
cells during their first encounter with Ag was shown to significantly
alter the balance of Th1/Th2 cytokines, and this phenotype was
maintained during subsequent stimulations in the absence of added
hormones. These findings indicate that the transition from naive to
memory/effector T cells is a critical time for the development of
gender differences in the T cell response to Ags. The effects of
androgens on immunocompetent cell function are further supported in
this report by the detection of androgen receptor mRNA in
CD4+ T cells and Mac-1+ macrophages. These
results suggest that androgens can directly alter the development of
effector T cells and may play an important role in governing gender
differences in the immune response and susceptibility to autoimmune
disease. Gender differences in EAE
Gender differences in murine EAE parallel gender differences known
to occur in the human disease MS (26, 28, 29). Although the mechanisms
for increased susceptibility of disease in females are poorly
understood, findings from recent studies suggest that differential
induction of CD4+ T cell subsets may be involved (19, 29).
Consistent with these reports, we found that immunization of male SJL
mice with PLP 139–151 induced Ag-specific T cells that secreted high
levels of IL-10. In contrast, immunization of age-matched female mice
induced T cells that secreted high levels of IFN-. Subsequent
transfer of female PLP 139–151-specific T cell lines induced severe
EAE symptoms, while transfer of male T cell lines induced only mild
disease. The diminished severity of EAE caused by male T cells was most
likely due, at least in part, to their increased production of IL-10.
Not only has IL-10 been shown to inhibit inflammatory Th1 responses
(13, 30), protection from EAE has been induced by treatment with IL-10
(31), and anti-IL-10 Ab therapy has been shown to exacerbate EAE
(32). Our data are the first to show a sex-dependent polarization in
the T cell response following immunization with an encephalitogenic
peptide.
Regulation of immune cell function by sex hormones
A role for gonadal hormones in the immunoregulation of
encephalomyelitis is supported by recent observations in the EAE model.
Pregnancy has been shown to protect animals from EAE (33, 34), and
estrogen administered at levels equal to those found during pregnancy
can suppress EAE (17, 18). Castration of male animals increases the
severity of EAE (35), and androgens have been shown to reduce the
incidence and severity of disease (19). Androgens and estrogens are
clearly involved in immunoregulation. Sex hormones have been shown to
inhibit delayed-type hypersensitivity reactions (36), suppress Ag- and
mitogen-induced T cell proliferation (37, 38), and alter general
patterns of cytokine secretion (39). In the present study, we
established that sex hormones can have direct effects on T cell
cytokine synthesis and the severity of adoptively transferred EAE.
Physiologic concentrations of androgens (for male mice) were found to
inhibit IFN- and enhance IL-10 secretion by PLP 139–151-specific
CD4+ T cells. Adoptive transfer of female T cell lines
selected in the presence of androgen induced less severe EAE than
untreated female T cell lines, a response that could be attributed to a
decrease in proinflammatory cytokine synthesis. Changes in cytokine
synthesis were more robust when the cells were treated during their
first in vitro stimulation (data not shown), suggesting that immature T
cells are more sensitive to the influence of androgens. To investigate
this point further, we examined the effects of androgen treatment on
naive TCR transgenic T cells. Androgen treatment of naive T cells
during their first encounter with Ag caused a skewing toward Th2
cytokines, and this shift was maintained in the absence of hormone
during subsequent stimulations. These findings support the concept that
gender differences in EAE are formed, at least in part, by sex hormones
in the lymphoid microenvironment during the development of the
encephalitogenic T cell response.
Mechanisms of sex hormone actions
The mechanisms by which gonadal hormones are able to regulate
immune cell function remain unclear. We have shown that androgens can
regulate the expression of selected gene products since testosterone
and DHT alter the synthesis of specific cytokines without effecting the
expression of gene products associated with cell survival or
proliferation. This idea finds support in recent studies showing that
estrogen can augment the activity of the IFN- promotor. Fox et al.
(40) found two or more functional estrogen response elements lying
0.5–3.2 kb upstream from the start of the IFN- transcript. Although
estrogen or androgen response elements have yet to be discovered in
other cytokine gene complexes, it seems likely that they will.
The direct influence of sex hormones on immunocompetent cell
function is further supported by evidence demonstrating sex hormone
receptors in Ag-responsive cell types. Sex hormone receptors have been
detected in splenocytes, thymocytes, and peripheral blood cells
(41, 42, 43). Androgen receptor is expressed in all classes of T cells
defined by the markers CD4 and CD8 (20). It is also clear from both
clinical and experimental systems that sex hormones have direct effects
on CD4+ T cells. When T cells were stimulated by
anti-CD3 Ab (in the absence of APC), DHT was shown to decrease
IFN-, IL-4, and IL-5 production (16). However, this effect could not
be induced by testosterone; 5 reduction of testosterone to DHT was
necessary, a function thought to be performed by macrophages.
Macrophages may play a critical role in mediating the immune response
to sex hormones by metabolizing inactive (or less active) precursor
hormones to more active forms. Sex hormones may also alter the ability
of the macrophages to function as APCs. Estrogen receptors have been
detected in rat and human macrophages (21), and ours is the first
report of androgen receptor expression in murine macrophages. Sex
hormones have been shown to regulate macrophage phagocytic activity
(44), and the production of IL-1 (45) and TNF (46). It is conceivable
that changes in cytokine secretion could be mediated by the actions of
sex hormones on the APC. Androgens and/or estrogens may regulate the
expression of MHC class II, or affect costimulation and cytokine
synthesis, perhaps altering the function of T cells and/or other
immunocompetent cells.
In summary, the results of this study provide evidence to support the concept that gonadal hormones interact directly with immunocompetent cells during the maturation of an encephalitogenic immune response. This mechanism could be an important factor influencing the development of gender differences in autoimmunity.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Bruce F. Bebo, Jr., Department of Veterans Affairs, Neuroimmunology Research R&D-31, 3710 SW US Veterans Hospital Rd., Portland, OR 97201. E-mail address:
3 Abbreviations used in this paper: MS, multiple sclerosis; DHT, dihydrotestosterone; EAE, experimental autoimmune encephalomyelitis; PLP, proteolipid protein, MBP, Myelin basic protein.
Received for publication April 20, 1998. Accepted for publication September 1, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4 integrin by CD4 T cells is required for their entry into brain parenchyma. J. Exp. Med. 177:57.-interferon, but not IL-2 by activated murine T cells. Blood 78:688.-ethinylestradiol: an immunological study in the Lewis rat. Int. Arch. Allergy Immunol. 102:133.[Medline]
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 T. L. Guo, J. A. McCay, L. X. Zhang, R. D. Brown, L. You, N. A. Karrow, D. R. Germolec, and K. L. White Jr. Genistein Modulates Immune Responses and Increases Host Resistance to B16F10 Tumor in Adult Female B6C3F1 Mice J. Nutr., December 1, 2001; 131(12): 3251 - 3258. [Abstract] [Full Text] [PDF]
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 J. Matsuda, M. T. Vanier, Y. Saito, K. Suzuki, and K. Suzuki Dramatic phenotypic improvement during pregnancy in a genetic leukodystrophy: estrogen appears to be a critical factor Hum. Mol. Genet., November 1, 2001; 10(23): 2709 - 2715. [Abstract] [Full Text] [PDF]
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G. G. Burrows, Y. K. Chou, C. Wang, J. W. Chang, T. P. Finn, N. E. Culbertson, J. Kim, D. N. Bourdette, D. A. Lewinsohn, D. M. Lewinsohn, et al. Rudimentary TCR Signaling Triggers Default IL-10 Secretion by Human Th1 Cells J. Immunol., October 15, 2001; 167(8): 4386 - 4395. [Abstract] [Full Text] [PDF]
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S. M. Liva and R. R. Voskuhl Testosterone Acts Directly on CD4+ T Lymphocytes to Increase IL-10 Production J. Immunol., August 15, 2001; 167(4): 2060 - 2067. [Abstract] [Full Text] [PDF]
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 C. W. Roberts, W. Walker, and J. Alexander Sex-Associated Hormones and Immunity to Protozoan Parasites Clin. Microbiol. Rev., July 1, 2001; 14(3): 476 - 488. [Abstract] [Full Text] [PDF]
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A. Ito, B. F. Bebo Jr., A. Matejuk, A. Zamora, M. Silverman, A. Fyfe-Johnson, and H. Offner Estrogen Treatment Down-Regulates TNF-{{alpha}} Production and Reduces the Severity of Experimental Autoimmune Encephalomyelitis in Cytokine Knockout Mice J. Immunol., July 1, 2001; 167(1): 542 - 552. [Abstract] [Full Text] [PDF]
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B. F. Bebo Jr., A. Fyfe-Johnson, K. Adlard, A. G. Beam, A. A. Vandenbark, and H. Offner Low-Dose Estrogen Therapy Ameliorates Experimental Autoimmune Encephalomyelitis in Two Different Inbred Mouse Strains J. Immunol., February 1, 2001; 166(3): 2080 - 2089. [Abstract] [Full Text] [PDF]
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R. J. Butterfield, E. P. Blankenhorn, R. J. Roper, J. F. Zachary, R. W. Doerge, and C. Teuscher Identification of Genetic Loci Controlling the Characteristics and Severity of Brain and Spinal Cord Lesions in Experimental Allergic Encephalomyelitis Am. J. Pathol., August 1, 2000; 157(2): 637 - 645. [Abstract] [Full Text] [PDF]
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S. C. Wilcoxen, E. Kirkman, K. C. Dowdell, and S. A. Stohlman Gender-Dependent IL-12 Secretion by APC Is Regulated by IL-10 J. Immunol., June 15, 2000; 164(12): 6237 - 6243. [Abstract] [Full Text] [PDF]
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T. W. Klein, C. A. Newton, N. Nakachi, and H. Friedman {Delta}9-Tetrahydrocannabinol Treatment Suppresses Immunity and Early IFN-{gamma}, IL-12, and IL-12 Receptor {beta}2 Responses to Legionella pneumophila Infection J. Immunol., June 15, 2000; 164(12): 6461 - 6466. [Abstract] [Full Text] [PDF]
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