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Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire 03756
Address all correspondence and requests for reprints to: Dr. C. R. Wira, Department of Physiology, Dartmouth Medical School, Borwell Building, 1 Medical Center Drive, Lebanon, New Hampshire 03756-0001.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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An effective immune response requires that antigen-presenting cells (APCs) process antigen and present it to T cells to induce T cell activation (4, 5). For an immune response to be initiated, exogenous antigen is internalized, processed, and returned to the cell surface in association with major histocompatibility complex class II for recognition by CD4+ T cells (6). Exogenous antigen can also stimulate class I-restricted T cell activation after uptake by APCs via a phagocytic pathway (7). After antigen presentation, lymphocyte effector functions (including cytokine production, cytotoxicity, and antibody synthesis) are activated.
Previous studies have shown that the reproductive tract is an inductive site for immune responses. Using inactivated polio vaccine, Ogra and Ogra (8) demonstrated that antigen placed in the uterus and vagina of women resulted in specific antibodies in uterine and cervicovaginal secretions. In animals (for reviews, see Refs. 9, 10), a variety of antigens, placed in both the lower and upper reproductive tract, induce local IgA and IgG antibodies in uterine and cervicovaginal secretions. Although optimal conditions and sites of immunization remain to be identified, these studies demonstrate that immune responses can be elicited by local immunization within the female reproductive tract. What remains to be established is the way induction of immune responses is regulated to meet the challenges of maternal protection and perpetuation of the species.
Our studies in the rat demonstrate that the afferent arm of the
mucosal immune system in the female reproductive tract is under
hormonal control (11, 12). These studies showed that antigen
presentation by epithelial and stromal cells in the uterus and isolated
cells from the vagina varies with the stage of the estrous cycle and is
under hormone and cytokine control. In the uterus, antigen presentation
by epithelial cells increases at proestrus, the stage of the
reproductive cycle when blood estradiol levels are known to be
elevated, and after the administration of estradiol to ovariectomized
rats (12). In contrast, antigen presentation by uterine stromal cells
is inhibited by estradiol (11, 12). In the vagina, antigen
presentation is inhibited in response to estradiol and reversed when
progesterone is given along with estradiol (13). In other studies, we
found that antigen presentation in the uterus increases when
ovariectomized rats are treated with IFN
or IL-6 (12).
The overall objective of the present study was to examine the regulation by estradiol of antigen presentation in the vagina of the rat. The goals of this study were to: 1) measure the effect, of dose and length of time of estradiol administration, on antigen presentation by vaginal cells to OVA-specific T cells; 2) examine the effect of estradiol on MHC class II expression and the numbers of macrophage/dendritic cells/granulocytes in the vagina at the time of antigen presentation; and 3) determine whether APCs in the vagina act synergistically with other APCs to enhance antigen presentation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Preparation of uterine and vaginal cells
Vaginal cells were prepared by incubation with 0.25%
trypsin/2.5% pancreatin (Life Technologies, Grand Island,
NY) for 60 min at 4 C and for 60 min at 20 C before separation by mesh
sieve (250 µm pore size), as previously described (13). Cells were
aspirated through 18- and 20-gauge needles to prepare isolated
cells before resuspension in proliferation medium consisting of
RPMI-1640 (Life Technologies) containing 25 mM
HEPES supplemented with 10% FBS (HyClone Laboratories, Inc., Logan, UT), 5% NCTC 109, 5
x10-5 M 2-mercaptoethanol, 2
mM L-glutamine, 100 µg/ml streptomycin, 100
U/ml penicillin, and 2.5 µg/ml Amphotericin
B.
Isolation and purification of T lymphocytes and
thymus-adherent cells
T cell lines for in vitro studies were prepared from
the lymph nodes of Lewis rats injected with OVA-complete Freund’s
adjuvant (FCA) emulsion into the footpads (100 µg OVA in 100 µl PBS
and 100 µl FCA per rat). After 9 days, paraaortic and popliteal lymph
nodes were isolated, and lymphocytes prepared for cell culture, as
described previously (11). Briefly, T cells were incubated in
initiation medium (proliferation medium containing 200 µg/ml OVA with
1% rat serum) for 3 days; after which, cells were separated by density
centrifugation and cultured in proliferation medium supplemented with
5% supernatant from rat spleen cells cultured with 5 µg/ml
concanavalin A (Con A). After 7–10 days incubation, cells were
restimulated with OVA, in the presence of thymus cells, to increase T
cell numbers and were then frozen in liquid nitrogen until assays were
performed.
Because the thymus gland of the rat is a rich source of dendritic cells, adherent cells were prepared as follows: Thymus glands (4–5/group) were dispersed by mincing with forceps in Dulbecco’s PBS. After debris was allowed to settle for 2 min, cells were centrifuged (500 x g for 7 min) and washed in Dulbecco’s PBS before resuspension in proliferation medium at a concentration of 3 ml per thymus. To isolate the APC population of monocytes/macrophages and dendritic cells, the suspension was diluted 1:20, plated (20 ml) onto plastic Petri dishes (150-mm diameter) and incubated, 1 h at 37 C, for APCs to adhere to the plastic. Unattached cells were removed by two washes with media, after which, attached cells were released by scraping with a rubber scraper (Costar, Cambridge, MA) and were resuspended in fresh medium.
Antigen presentation assays
To measure antigen presentation, OVA-sensitized T cells (1
x 105 cells/100 µl), in proliferation medium,
were cultured in triplicate wells, in 96-well microtiter plates, with
irradiated epithelial cells from the uterus or vaginal cells (1 x
105 cells/100 µl) in the presence of OVA (50
µl) at varying concentrations (APC+T+OVA) (11). APC (uterine/vaginal
cells) populations were irradiated, before the start of antigen
presentation, with 4000 rads to prevent their proliferation. Controls
included in all experiments were: APCs incubated with T cells in the
absence of ovalbumin (OVA; APC+T), APCs incubated with OVA
(APC+OVA), and T cells incubated with OVA (T+OVA). After 48 h of
incubation at 37 C, T lymphocyte proliferation was measured by
3H-thymidine uptake. Each well received 1 µCi
of 3H-thymidine (50 µl), 20–24 h before the
termination of each experiment. Cells in individual wells were
transferred onto glass fiber filtermats with a cell harvester (Skatron,
Sterling, VA). Radioactivity incorporated into cells was measured in a
liquid scintillation counter (Packard, Meriden, CT). The significance
of the differences between experimental and control groups was
calculated by Student’s t test.
Immunohistochemical analysis
Uterus and vagina were excised, trimmed below the cervix, and
washed in cold saline (0.9% NaCl) before AMeX processing (a procedure
that uses acetone, methyl alcohol, and xylene) (14). Briefly, 6
mm-sections were cut on a microtome and placed on glass slides coated
with 1.5% BSA. Sections were deparaffinized in xylene and rehydrated
through ethyl alcohol grades. Rehydrated sections were washed in 0.01
M PBS/BSA (1 mg/ml). Nonspecific binding was blocked by
incubating sections with 1% horse serum for 20 min at room
temperature. Monoclonal antibodies used were mouse antirat Ia (OX-6)
and mouse antirat macrophages, granulocytes, and dendritic cells
(OX-41) (Harlan Bioproducts for Science, Inc.,
Indianapolis, IN). Sections were stained with primary antibody at a
dilution of 1:200 for 30 min, rinsed, and incubated with horse
antimouse Ig conjugated to biotin (1:200 dilution) for an additional 30
min. Other sections were stained with isotype control Igs at an
equivalent concentration, instead of primary antibody. Horse antimouse
IgG (rat adsorbed), conjugated to biotin, was obtained from
Vector Laboratories, Inc., Burlingame, CA. Avidin-biotin
coupled to alkaline phosphatase or peroxidase (ABC Elite kit,
Vector Laboratories, Inc.), followed by Vector Red or
diaminobenzidine (substrates from Vector Laboratories, Inc.), respectively, was used to reveal antigen localization.
Slides were counterstained with hematoxylin, dehydrated in alcohol, and
mounted in Permount medium before being examined under the
microscope.
Spleen cell proliferation
To measure spleen cell proliferation, spleens were removed
aseptically from animals, and single cell suspensions were prepared by
teasing with sterile forceps. Tissue debris was allowed to settle for 2
min, and the supernatant containing single cells was spun at 500
x g for 10 min. Spleen cells were treated with
NH4Cl solution for 5 min to lyse the RBC, as
previously described (15). Cells were washed three times with RPMI-1640
medium containing 10% FBS and were plated into 96-well chambers at a
concentration of 5 x 105 cells per well. A
final concentration of 1 µg/ml concanavalin A (Con A,
Sigma, St. Louis, MO), 10 µg/ml phytohemagglutinin (PHA,
Sigma), or 30 µg/ml lipopolysaccharide (LPS, Difco
Laboratories, Detroit, MI) was added to each well. Proliferative
responses were measured by uptake of 1 µCi/well of
3H-thymidine for the last 24 h of a
3-day culture. Results are reported as mean cpm ±
SE of triplicate cultures. Each experiment was
repeated four times.
Hormone treatment and antibodies
Estradiol-17ß, from Calbiochem (La Jolla, CA),
was initially dissolved in ethanol, evaporated to dryness, and then
resuspended in 0.9% saline. Control animals received only saline. To
correct for the alcohol present in the estradiol preparation, an
equivalent amount of ethanol was evaporated in flasks used to prepare
saline.
Purified antirat B7.1 (CD 80) and B7.2 (CD 86) antibodies were purchased from PharMingen (San Diego, CA). Antibodies were used at a final concentration of approximately 10 µg/ml. MOPC-21 (Sigma) and P3 myeloma supernatant (a generous gift from Dr. Michael Fanger, Department of Microbiology, Dartmouth Medical School, Lebanon, NH) were used as IgG1 isotype controls at the same concentration.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, antigen presentation by vaginal
cells is not affected with 0.01 µg/day but is inhibited with 0.1- and
1.0-µg doses of estradiol. In all cases, thymidine incorporation in
controls was lower than that seen in Fig. 1, when APCs were incubated
with T cells without OVA. Irrespective of whether vaginal cells were
from saline- or estradiol-treated rats, T cell proliferation was low,
in the absence of OVA. In other studies (not shown), we found that
increasing the dose of estradiol to 10 µg/day had no further effect
on vaginal antigen presentation beyond that seen with 1.0 µg/day.
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, treatment with a single injection of estradiol inhibits vaginal cell
antigen presentation to OVA-specific T cells by 75% of that seen with
APCs from saline controls. Treatment for 2 additional days had no
significant effect on antigen presentation beyond that seen at day 1.
To more fully characterize the onset of the inhibitory response in the
vagina, ovariectomized animals were injected with a single dose of
estradiol (1 µg) and killed 4, 10, and 24 h later. As seen in
Fig. 3, inhibition of antigen
presentation was not detected at 4 and 10 h but was significant,
at 24 h following hormone treatment, relative to saline controls.
As with our long-term course study (Fig. 2), we found that antigen
presentation in response to estradiol was inhibited by 75% of that
seen with saline controls within 24 h of hormone treatment. These
studies indicate that a time interval of 10–24 h is needed to observe
an inhibition by estradiol of vaginal cell antigen presentation.
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, A and B. Based
on visual analysis, these studies suggest that, in the absence of
estradiol (saline controls), numerous MHC Class-II positive cells (OX-6
positive) are distributed in the stroma below the squamous epithelial
layer. Estradiol treatment (1 µg/day for 3 days) seems to have no
effect on the number of MHC Class-II positive cells, relative to saline
controls (Fig. 4D); OX-6 positive cells were observed with the same
frequency as those seen in saline-treated animals. Occasional clusters
of MHC class II positive cells, however, were observed adjacent to the
epithelial layer in estradiol-treated animals (not shown). Compared
with large numbers of MHC Class II positive cells in the vaginal
tissues of saline-treated rats, only limited numbers of macrophages,
dendritic cells, and granulocytes (localized by OX-41 antibody) were
seen in these tissues (Fig. 4E). In contrast to Class II, increased
numbers of OX-41 positive cells were localized in the subepithelial
stroma of vagina from estradiol-treated animals (Fig. 4F). This study
suggests that estradiol has a pronounced effect on increasing the
number of macrophages, dendritic cells, and granulocytes in vaginal
tissues without increasing or decreasing the number of Class II
positive cells in the lower reproductive tract.
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, which is
representative of three separate experiments, the addition of murine
monoclonal antibodies to B7.1 and B7.2 significantly lowered antigen
presentation of OVA to OVA-specific T cells. In other experiments (not
shown), when vaginal cells from saline- and/or estradiol-treated
ovariectomized rats were incubated with OVA-specific T cells and
anti-class II antibodies, antigen presentation was inhibited by OX-6
(anti-class II Ia), relative to that seen with isotype control
(IgG1).
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(solid
bar). When vaginal cells (APCs, 1 x
105) from saline-treated rats were cultured with
thymus-adherent cells along with OVA-specific T cells and OVA
(APC/TAPC+T+OVA), antigen presentation was additive. Also shown in Fig. 6 is the inhibitory effect of estradiol treatment (2 and 20 µg) on
vaginal cell antigen presentation. In contrast, when vaginal cells from
estradiol-treated rats are incubated with thymus-adherent cells,
antigen presentation increases significantly beyond that seen with
vaginal cells (APC+T+OVA) or thymus cells (TAPC+T+OVA) alone. This
synergistic effect, which was observed in four separate experiments,
suggests that coculture of vaginal cells with thymus-adherent cells
enhances antigen presentation of one or both APCs, under conditions in
which estradiol given in situ is inhibiting vaginal antigen
presentation.
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, CM prepared
from saline-and estradiol-treated animals, when added to
thymus-adherent cells incubated with OVA-specific T cells,
significantly increases antigen presentation beyond that seen with
APC+T+OVA alone. This response was observed in three separate
experiments. In all studies, CM prepared from saline-treated animals
had a more pronounced stimulatory effect on antigen presentation by
thymus cells than did CM prepared from the vaginal cells of
estradiol-treated animals. Vaginal cells used to prepare CM were tested
independently for their ability to present antigen to T cells. In both
studies, estradiol treatment was found to have a pronounced inhibitory
effect, relative to that seen with saline controls. These findings
indicate that vaginal cells from saline- and estradiol-treated rats
produce a soluble factor(s) that enhances TAPC antigen presentation.
Because the response with CM from estradiol-treated rats was lower than
that seen with CM from saline controls, it suggests that estradiol
either decreased the production of the soluble factor or led to the
production by vaginal cells of a separate inhibitory factor that
reversed the effect seen with CM from saline controls.
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are
representative of four separate experiments. As seen in Fig. 8A, vaginal cells from saline-treated animals, when added to spleen cells
in the presence of Con A, had a 2- to 3-fold higher proliferation than
that seen with spleen cells alone [ four out of four (4/4)
experiments]. In contrast, the addition of vaginal cells from
estradiol-treated rats had either a slight stimulatory effect (1/4) or
no effect on Con A-stimulated spleen cell mitogenesis (3/4).
Proliferation of spleen cells in the absence of mitogens, vaginal cells
in the presence of mitogen, vaginal and spleen cells alone, vaginal
cells alone, and spleen cells alone were either low or not different
from background. In response to PHA (Fig. 8B), spleen cells had a
significantly higher proliferative response when vaginal cells from
saline-treated rats were present (3/4) and a significantly lower
response with estradiol-treated vaginal cells (4/4). In contrast,
spleen cell proliferation in the presence of LPS, a known B cell
mitogen, was significantly lower when vaginal cells from saline- or
estradiol-treated animals were present (4/4), than that seen in the
absence of vaginal cells (Fig. 8C).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous studies from our laboratory have shown that the female reproductive tract is an inductive site for initiating immune responses. Both the uterus and vagina contain APCs that are functionally capable of presenting antigen to OVA-specific T cells (11, 13). We found that antigen presentation by uterine epithelial cells is increased in intact rats at proestrus, the stage during the estrous cycle when estradiol levels are known to be elevated, and in ovariectomized animals treated with estradiol (11). In contrast, antigen presentation by uterine stromal cells and vaginal cells is inhibited by estradiol (13). The data presented in this article extend these findings by demonstrating the rapid inhibition by estradiol of vaginal cell antigen presentation. In other studies, we found that the release of estradiol by the ovary, on the afternoon of day 2 diestrus, precedes by 24 h increases in IgA and pIgR levels in the uterus (16). Our finding of a maximal inhibitory response to estradiol within 24 h, in the present study, suggests that estradiol release by the ovary at diestrus is responsible for the inhibition of antigen presentation in the vagina that occurs at proestrus and estrus (13).
Dendritic cells are known to act synergistically with other APCs in presenting antigen to T cells (17, 18). Macrophages in the lung, for example, which are known to be weak APCs, are thought to produce antigenic peptides that are picked up by dendritic cells and presented to T cells (18). We found that uterine epithelial and/or stromal cells, when cocultured with thymus-adherent cells, enhance antigen presentation beyond that seen by uterine cells alone or thymus cells alone (11). In the present study, antigen presentation is enhanced synergistically when vaginal cells are coincubated with dendritic-like cells. These studies demonstrate that APCs in both the upper and lower reproductive tract interact synergistically with APCs from other sites in the body. Because dendritic cells present antigen at sites distant from the site of antigen uptake (19), these studies suggest that cooperative interactions between different APCs in the reproductive tract (dendritic cells, macrophages, B cells, and epithelial cells) may occur to optimize chances for mounting an effective immune response in the female reproductive tract.
Coculture of spleen cells and vaginal cells from saline- and estradiol-treated rats has a profound effect on mitogenesis and varies with the mitogen used. For example, when Con A and/or PHA, two T cell mitogens, are added to spleen cells along with vaginal cells from saline-treated rats, spleen cell proliferation is enhanced 2–2.5 times beyond that seen in the absence of vaginal cells. In contrast, vaginal cells from estradiol-treated rats, under the same conditions, either inhibit or have no effect on mitogenesis. Moreover, when LPS (a known B cell mitogen) is present, vaginal cells from saline- and estradiol-treated rats inhibit spleen cell proliferation. These findings indicate that, depending on the immune cell stimulated (T cells, B cells, or APCs), vaginal cells have separate and distinct effects on cell proliferation.
Unexpectedly, we found that antigen presentation by thymus-adherent cells is stimulated by CM prepared from isolated vaginal cells of saline- and estradiol-treated rats. Though antigen presentation was increased in both cases, the magnitude of the response was significantly greater with CM from saline-treated animals than that seen after estradiol treatment. What is remarkable is that, in 3/3 experiments, antigen presentation by vaginal cells used to prepare the CM was fully inhibited in terms of their ability to present antigen. Our finding that CM from the vaginal cells of estradiol-treated rats is less stimulatory than that seen with control CM suggests either that the soluble factor (cytokine) involved is inhibited by estradiol treatment or that multiple factors (stimulatory vs. inhibitory) are involved. One possible interpretation of this is that, at a time when estradiol is inhibiting antigen presentation in the vagina, it is stimulating APCs or other cells in the vagina, to produce cytokines that enhance thymus cell antigen presentation. Identification of the cytokine(s) involved, the cells responsible for cytokine production, and the cells (APCs and/or T cells) that respond to the cytokine(s) produced remain to be determined.
These studies suggest that MHC class II expression on vaginal APCs is not the rate-limiting step by which estradiol inhibits antigen presentation, because inhibition is complete at a time (24 h) when vaginal MHC class II expression remains unchanged. Others have shown that, in addition to MHC class II, costimulatory molecules (including ICAM-1, CD4, CD40, and CD40 ligand) play a central role in the transduction of signals from APCs to T cells (20, 21). Our finding that antigen presentation by vaginal cells is inhibited when antibodies to B7.1 and B7.2 are added to the culture media indicates that antigen presentation by vaginal APCs is mediated through these transmembrane costimulatory molecules. B7.1 and B7.2 proteins are costimulatory molecules present on the surfaces of APCs and are important for the activation of T cells specific for both foreign antigens and autoantigens (22). Our ongoing studies are aimed at determining whether estradiol inhibits antigen presentation by vaginal cells by down-regulating the expression of B7.1 and B7.2, as well as other costimulatory molecules. Unexpectedly, we found that estradiol-induced inhibition of antigen presentation is maximal at a time when, based on visual examination of stained tissue sections, Class II positive cells seem to remain constant in the vagina and macrophages/dendritic cells/granulocytes increase in response to estradiol treatment. This paradoxical observation suggests either that estradiol is lowering class II expression on those cells in the vagina or that granulocytes entering the vagina express low levels of Class II. Further studies are needed to resolve this finding.
Our findings suggest that local immunosuppression in the vagina
protects against immune responses to sperm, which could lead to
infertility. We have previously found that antigen presentation in the
vagina of the rat is inhibited at estrus, when mating is most likely to
occur (13). Because semen is deposited in the vagina at this time, our
findings suggest that the presence of allogeneic sperm in the vagina
coincides with a transient down-regulation of the afferent arm of the
immune system, possibly to decrease the chance of sensitization to
sperm. That immune suppression does occur in the female reproductive
tract is well documented at the time of implantation and throughout
pregnancy (23, 24, 25, 26). Mediated, in part, through the actions of TGF-ß,
NK cells are suppressed at the site of implantation (27, 28). Others
have suggested a potential role for IFN in the uterus of the
pregnant mouse, which would be to up-regulate class I expression to
mask trophoblastic cells from being killed by NK cells (29). Our
findings extend these observations by demonstrating that, in addition
to that seen in the uterus, localized suppression also occurs in the
vagina, in response to estradiol.
These findings may have particular importance in terms of susceptibility to sexually transmitted diseases. Studies by Marx et al. (30) demonstrated that primate susceptibility to simian immunodeficiency virus (SIV), the causative agent of AIDS-like symptoms in Macaques, is increased 8-fold when animals are treated with progesterone before intravaginal infection. These studies suggested that progesterone thins the layer of squamous cells in the vagina, possibly to increase vaginal penetration by SIV. An alternative possibility, suggested by our findings, is that progesterone suppresses antigen recognition and presentation in the vagina, which, in turn, leads to the rapid progression of disease. We and others previously have shown that estradiol and/or progesterone stimulate and inhibit mucosal immunity in the female reproductive tract and that regulation varies with the site in the reproductive tract studied and the species analyzed (10, 31, 32). Recently, we found that progesterone pretreatment of adult female rats is required for the induction of uterine and vaginal chlamydial infection (33). In other species, estradiol leads to enhanced susceptibility to infection in the guinea pig and human (34). Whether sex hormones enhance human susceptibility to bacterial and viral infection in the female reproductive tract by suppressing immune recognition of potential pathogens remains to be determined.
With the identification of the reproductive tract as an inductive site for immune responses, our studies in the rat suggest that the stage of the menstrual cycle in women may be an important determinant in the successful use of mucosal vaccines against sexually transmitted diseases, including HIV. In other studies, we have found that APCs in the human fallopian tube, uterus, cervix, and vagina are functionally able to present tetanus toxoid antigen to autologous T cells (35). These studies led to the suggestion that antigen presentation in the human female reproductive tract may be under hormonal control, because tissues from some patients (ovary, Fallopian tube, endocervix, and ectocervix) were unable to present antigen to T cells. Whether this reflects changes in hormone balance during the menstrual cycle remains to be established.
In conclusion, we report that the afferent arm of the mucosal immune system in the rat vagina is under hormonal control. These studies indicate that control of antigen presentation by estradiol in the vagina is separate and distinct from that seen in the uterus. Further, these findings suggest that endocrine balance, which varies with the stage of the menstrual cycle, menopause, the use of oral contraceptives, and hormone replacement therapy, may be important determinants in the recognition and response of the mucosal immune system to potential pathogens.
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Acknowledgments |
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Footnotes |
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Received December 2, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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of secretory component and immunoglobulin A in uterine
secretions and proliferation of lymphocytes from spleen. Endocrinology 129:2915–2923[Abstract]
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