Hindawi Publishing Corporation
BioMed Research International
Volume 2013, Article ID 570158, 9 pages
Sex-AssociatedExpressionof Co-Stimulatory MoleculesCD80,
CD86, and Accessory Molecules,PDL-1,PDL-2and MHC-II, in
F480+ Macrophagesduring Murine Cysticercosis
1Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, AP 70228,
04510 México, DF, Mexico
2Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, 04510 México, DF, Mexico
3Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México,
Avenida de Los Barrios No. 1 Los Reyes Iztacala, 54090 Tlalnepantla de Baz, MEX, Mexico
Correspondence should be addressed to Jorge Morales-Montor; firstname.lastname@example.org
Received 31 August 2012; Revised 1 November 2012; Accepted 15 November 2012
Academic Editor: Miriam Rodríguez-Sosa
Copyright © 2013 Cristián Togno-Peirce et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Macrophages are critically involved in the interaction between T. crassiceps and the murine host immune system. Also, a strong
gender-associated susceptibility to murine cysticercosis has been reported. Here, we examined the sex-associated expression of
molecules MHC-II, CD80, CD86, PD-L1, and PD-L2 on peritoneal F4/80himacrophages of BALB/c mice infected with Taenia
and CD80 that was dependent from the sex of the host. ese �ndings suggest that macrophage recruitment at early time points
during T. crassiceps infection is a possible mechanism that underlies the differential sex-associated susceptibility displayed by the
�ender of the host in�uences the outcome of many parasitic
diseases. For example, in Leishmania major infection, female
mice mount a strong 1 response and resolve the infection.
In contrast, male mice mount a 2-dominant response and
develop chronic lesions . In other protozoan infections,
such as toxoplasmosis, an opposite �nding was observed:
female mice succumb to Toxoplasma gondii infection despite
a 1 response, whereas male mice display resistance and
survive for a longer period of time to similar challenges .
In helminth infections, the gender of the host also
plays an important role in the outcome of the infection by
inducing different responses depending on the sex [3, 4].
In contrast to the well-described adaptive immunity against
these helminthic infections, the role of macrophages (M𝜙𝜙s)
is still unclear. ere have been only limited studies on the
macrophage response to helminth-derived antigens and the
impact of these responses on the outcome of the infection is
not known. Much lesser information exists in relation to the
role of sex on the macrophage response to helminth-derived
A sexual dimorphism exists in the acquired immune
response against different pathologies and in many autoim-
and reproductive endocrine system . Moreover, reciprocal
factor that has an in�uence in parasite success [6, 7].
siceps [8, 9] is well known as a manageable experimental
system which explores the role of biological factors involved
2BioMed Research International
in host susceptibility . Interestingly, in T. crassiceps cys-
ticercosis, females of all strains of mice studied sustain larger
intensities of infection than males . At the same time, the
cellular immune response (1) is markedly diminished in
Estradiol is involved in the immunoendocrine regulation of
murine T. crassiceps cysticercosis as a major protagonist in
dependent cellular immune mechanisms that obstruct para-
site growth . Gonadectomy alters this resistance pattern
and makes intensities equal in both sexes by increasing
that of male mice and diminishing it in female mice .
In addition, the hormonal substitution of gonadectomized
proliferation, IL-2, and IFN-𝛾𝛾 production were depressed in
there was a signi�cant recovery of the splenocyte prolifer-
ation and 1 cytokine production on these animals. On
the other hand, mice treated with estradiol were not able to
induce these cellular responses .
Macrophages are phagocytic cells that are widely dis-
tributed on the organism and have an important role in the
in T cell activation through antigen presentation by the
expression of MHC molecules and costimulatory/inhibitory
molecules. It has been demonstrated that the expression
of MHC molecules and the expression of costimulatory
molecules such as B7-1 (CD80) and B7-2 (CD86) could
modulate T cell activation and 1/2 polarization during
infection and autoimmunity [17, 18]. Programmed death
ligand 1 (PD-L1) and programmed death ligand 2 (PD-
L2) have been related to alternate activated phenotype in
macrophages induced during Taenia crassiceps infection
. Macrophages also have a broad participation in the
development of the immune response to many pathogens,
particularly to helminthes  by polarizing T helper ()
cells activation in 1 or 2, and also have a role in
tissue remodeling and wound repair . In the context
of immunoendocrine communication, it has been shown
that sex steroids are able to modulate survival of human
macrophages cell lines , the recruitment of macrophages
to the site of in�ammation, and their effector functions .
on macrophages depends on the concentration, type, and the
it has been previously established that sex steroid effects
on macrophages depend on the expression of the androgen
receptor (AR) [25, 26], progesterone receptor (PR) , and
males and reconstitution of female mice with 17𝛽𝛽-estradiol
gonadectomized-parasitized mice of both genders, and aer
the reconstitution with testosterone or dihydrotestosterone,
increased parasite loads . Also, speci�c splenocyte cell
both types of estrogen receptor (ER𝛼𝛼 y ER𝛽𝛽) .
susceptibility/resistance in murine cysticercosis and also can
Since macrophages have been importantly involved in
response of molecules of early activation of recruited F4/80hi
macrophages, such as MHC-II, CD80, CD86, PD-L1, and
indeed there is a differential expression of these molecules in
2. Materials and Methods
2.1. Ethics Statement. e Animal Care and Use Committee
at the Instituto de Investigaciones Biomédicas evaluated
animal care and experimentation practices according to the
official Mexican regulations (NOM-062-ZOO-1999) in strict
accordance with the recommendations in the Guide for the
of Health (NIH and the Weatherall Report) of the USA.
e Ethics Committee of the Instituto de Investigaciones
Biomédicas approved this protocol (Permission Number
2.2. Animals and Experimental Infections. Male and female
BALB/cAnN (H2-d) inbred mice obtained from Harlan
(Mexico City) were used in all experiments. Animals were
housed in the animal care facilities at Instituto de Investiga-
ciones Biomédicas, (UNAM), under controlled conditions of
0700 and 1900. ey were fed Purina Diet 5015 (Purina, St.
Louis, MO) and given tap water ad libitum.
2.3. Aantigen Extraction and Infection. Metacestodes of Tae-
nia crassiceps of the ORF strain were harvested in aseptic
conditions from the peritoneal cavity of female BALB/cAnN
mice aer 4 months of infection. Metacestodes were washed
with cold sterile saline (Solución CS, Laboratorios PISA. S.A.
de C.V. [NaCl 0.9%]). T. crassiceps soluble extract (TcEx)
with a duration of 1s, by using an ultrasonic homogenizer
(Vibracell, SONICS & MATERIALS, Newtown, USA). e
homogenates were centrifuged at 20,000g for 30min at
metacestodes (30mL volume) with tree pulses of 60Hz
4∘C, and the supernatants containing saline-soluble antigens
tein concentration was estimated by Bradford protein kit
assay (BioRad). Sex-and age-matched mice were infected by
intraperitoneal (ip) injection with 20 small (approximately
were collected and frozen at −20∘C until further use. Pro-
TcEx in 300𝜇𝜇L saline or 300𝜇𝜇L saline as control. Six days
cells were collected for analysis.
2mm) nonbudding cysticerci/300𝜇𝜇L saline, with 400𝜇𝜇g
overdose of sevo�urane (Sevorane� Abbott) and peritoneal
aer-injection, animals were sacri�ced by inhalation of an
2.4. Isolation of Peritoneal Macrophages. Peritoneal exudate
cells (PECs) were obtained from saline, TcEx-treated, or 6-
day-T. crassiceps infected mice (BALB/c male or female)
by peritoneal lavage with 7mL of sterile ice-cold saline
hemocytometer. Viable cells were counted and adjusted
exclusion. Routinely viability was around over 95%.
washed twice with cold PBS. Aer two washes, the viable
cells were counted by trypan blue exclusion with a Neubauer
to 1×106cells/mL. Viability was measured by trypan blue
BioMed Research International3
2.5. Analysis of Cell Surface Markers in Macrophages. e
surface expression of macrophage markers was analyzed
using multicolor �ow cytometry. M𝜙𝜙s were suspended in
cold PBS containing 2% FCS and 0.02% NaN3. e Fc recep-
APC-conjugated mAbs against F4/80, PE-conjugated mAbs
against CD86 or PD-L2, PerCP-conjugated IA/IE (MHC-II),
PE-Cy5-conjugated CD80 or Biotin-conjugated PD-L1, and
PE-Cy5-conjugated Streptavidin. All Abs were purchased
from BioLegend (BioLegend, San Diego, CA, USA). A gate
including high forward light scatter (FSC)/high side light
a FACsCalibur �ow cytometer (Becton Dickinson) and data
analyzed with the FlowJo (Tree Star) soware. Absolute
numbers in all assays were calculated according to the
percentage of positive macrophages and the total numbers of
tors were blocked with anti-mouse CD16/CD32 for 20min
at 4∘C. e cells were washed and triple stained with an
2.6. Statistical Analysis. e data of the three replications of
each experiment were pooled and expressed as their average.
e data were analyzed using analysis of variance (ANOVA)
with sex (2 levels) and number of experiment (3 levels) as
independent variables and as dependent variables: the total
number of developed cysticerci and the expression of each
molecule. If signi�cant differences between treatments were
found by ANOVA, differences between the group means
using the residual variance estimated by ANOVA to test for
signi�cance. Differences were considered signi�cant when
𝑃𝑃 ? ????.
In order to determine the role of sex during early infection,
mice of both sexes were infected and sacri�ced 6 days aer-
infection. As previously reported , at this time point of
infection, there is no statistical difference in parasite loads
between males and females, though there is a slight trend in
is also consistent with the observation that sexual dimor�sm
begins aer the �rst week of infection in BALB/c mice .
cavity (site of infection) of saline-treated, TcEx, and infected
mice of both sexes. Total PECs recruitment in infected male
(Figure 2(b)) and their total number (Figure 2(c)), de�ned
differences in the percentage of F4/8?hicells between sexes
in the number of total M𝜙𝜙s during early infection, we
analyzed the population of PECs recruited to the peritoneal
mice is decreased (𝑃𝑃 ? ????) compared to infected females,
been previously involved in the susceptibility/resistance to
murine cysticercosis, we decided to analyze their percentage
by their high expression of F4/80 (F4/8?hi). We found no
(Figure 2(b)), but there was a marked increase in the total
number of M𝜙𝜙s detected in infected females with respect to
F 1: Parasite load obtained of Female (F) and male (M) mice.
Data show the number of parasites recovered from the peritoneal
cavity at 6 days post-infection. At this time of infection, animals did
not show the typical sexual dimorphism of this infection observed
in longer infection times. Each point represents individual parasite
infected males. is difference was not observed in the other
treatments (Figure 2(c)).
To characterize the phenotype of M𝜙𝜙s recruited of the
and PD-L1/PD-L2 (Figure 5) by �ow cytometry. In Figure
3(a), the percentage of MHC-II+ cells found is depicted.
ere is no difference associated to treatment or sex, in the
is no difference between animals, either by treatment or sex
In Figure 4, the analysis of the expression of CD80 and
CD86 is plotted. ere were no differences associated to sex
the total number of CD80+ or CD86+ M𝜙𝜙s that is observed
4(b) and 4(e)). We also compared the relative mean intensity
differences in the coestimulatory ability of these cells. We
found no differences between male and female mice in terms
of CD80 expression either by treatment or sex (Figure 4(c)).
female mice, even when these data did not show signi�cance
Finally we look for differences in the expression of PD-
peritoneal cavity of infected mice of both sexes, we look for
percentage of M𝜙𝜙s expressing these molecule. However, as
(a measure of the amount of the total MHC-II per cell), there
seen in the total number of PECs of infected female mice, the
in the percentage of M𝜙𝜙s expressing CD80 or CD86 (Figures
in infected mice; female mice show an increased number
of this population when compared to male mice (Figures
4(a) and 4(d)). However, there is a marked difference in
4BioMed Research International
Macrophages (×106) per individual
F 2: Kinetics of total peritoneal exudate cells (PECs) recovered from the peritoneum aer T. crassiceps infection. (a) Peritoneal cells
processed for �ow cytometry and analyzed. (b) Flow cytometry analysis shows that macrophages (F4/80hi) are recruited within 6 days p.i.
(d.p.i.). (c) Increased numbers are detected per individual associated to sex as infection progresses peritoneal exudate cells.
and 5(d), there were no differences in the percentage of PD-
L1 or PD-L2 expressing M𝜙𝜙s among males and females, but
CD80/86, there were also higher numbers of PD-L1- or PD-
there were differences among treatment: infection induced
a higher expression of PD-L1/2 than TcEx. As observed for
Given the reported importance of sex- and pregnancy-
associated hormones in the establishment and outcome of
parasitic diseases, this is an area of research that is likely
to grow. e important role that sex steroids plays dur-
ing murine cysticercosis has been previously demonstrated
in experiments in which gonadectomy, thymectomy, and
whole body irradiation showed that both the endocrine
and immune systems of the mice were involved in the
parasite load differences between the host sexes. Interest-
ingly orchidectomy in male mice raises parasite loads while
ovariectomy has the opposite effect; it increased them 3-fold
. ymus hindered parasite reproduction in both sexes
response to parasites and they can also function as effector
cells. e recruitment and activation of macrophages by
helminth-derived molecules initiate with the expression of
accessory molecules. ese immune mediators play crucial
roles in the development of immunity against a variety of
BioMed Research International5
Macrophages (×106) per individual
F 3: MHC-II characterization in M𝜙𝜙s recovered from the peritoneum aer T. crassiceps infection. MHC-II expression was determined
this molecule (relative mean intensity, MSR) (c) are shown.
on M𝜙𝜙s (F4/80hi) recruited aer 6 days of infection with 20 cysts of T. crassiceps. e percentage (a), total numbers (b), and the expression of
pathogens, but their role in helminthic infections is less well
understood [32, 33]. In this study, we found an increased
female BALB/c mice in comparison with male mice and
expressed MHC-II, the coestimulatory molecules CD80,
ever, the major difference that we found was associated to
did not exist. ere were more M𝜙𝜙s in infected females
phenotype observed in IL-12 KO mice  and suggest a
major role for macrophages in cysticercosis. e mechanism
underlying the differential expression of MHC-II, CD80,
CD86, PD-L1, and PD-L2 in our system remains to be
elucidated; however, it may be associated with an impaired
compared to those observed in infected males aer similar
stimulation. ese data are consistent with the susceptible
e relevance of these observations is highlighted by the
�nding that macrophages from BALB/c female mice became
more rapidly alternatively activated in T. crassiceps chronic
infection, whereas macrophages from male mice presented
a transient and incomplete alternate activation during early
infection . us, the presence and the persistence of
AAM𝜙𝜙 are another striking difference between the suscep-
androgen receptor (AR) [25, 26], progesterone receptor (PR)
tible and resistant sex of mice to T. crassiceps infection.
In the context of immunoendocrine communication, it
of human macrophages cell lines , the recruitment of
6BioMed Research International
Macrophages (×106) per individual
Macrophages (×106) per individual
F 4: CD80/CD86 characterization in M𝜙𝜙s recovered from the peritoneum aer T. crassiceps infection. Costimulatory molecules CD80
and(d), Total numbers (b) and (e), and the expression of these molecule (relative mean intensity, MSR) (c) and (f) are shown.
and CD86 expression was determined on M𝜙𝜙s (F4/80hi) recruited aer 6 days of infection with 20 cysts of T. crassiceps. e percentages (a)
macrophages to the site of in�ammation , and their
effector functions. As occurred with other immune cells,
the effect of sex steroids on macrophages depends on the
concentration, type, and the context in which macrophages
are studied .
For instance, in the murine model of incisional wound,
gonadectomy of females is associated to an increased in�am-
mation and delay in wound healing. is effect is due to the
fact that ovariectomy induces an increase in the secretion
of TNF-𝛼𝛼 and MIF, as well as in the number of in�ltrated
BioMed Research International7
Saline TcEx Infected
Macrophages (×106) per individual
Macrophages (×106) per individual
F 5: PD-L1/PD-L2 characterization in M𝜙𝜙s recovered of the peritoneum aer T. crassiceps infection. Inhibitory molecule, PD-L1, and
(d), total numbers (b and e), and the expression of these molecules (relative mean intensity, MSR) (c) and (f) are shown.
PD-L2 expression was determined on M𝜙𝜙s (F4/80hi) recruited aer 6 days of infection with 20 cysts of T. crassiceps. e percentages (a) and
macrophages at the site of the lesion. Also, the percentage
of alternatively activated macrophages is decreased [23, 36].
If castrated females are reconstituted with E2 concentrations
observed during estrous, then the production of TNF-𝛼𝛼,
cal levels of progesterone has a modest effect, in comparison
to the effect induced by estradiol, on the same parameters
studied . Moreover, sex steroides regulate the production
MIF, and the total number of in�ltrated macrophages in the
wounds are decreased. However, treatment with physiologi-
of nitric oxide (NO) by macrophages, in a dichotomic way.
At low concentrations, E2 stimulates the secretion of NO
by LPS-activated macrophages in vitro; however, at high
concentrations of E2, there is a decrease of NO [37, 38].
Furthermore, estradiol and to a lesser extent progesterone
decrease theactivity oftheenzymecatalase,a very important
modulator of the NO synthesis . As such, these data
may represent an important mechanism underlying the
immunomodulating effects of sex steroids.
8BioMed Research International
Previously, we showed that during murine cysticercosis,
an impressive feminization process is produced in the male
host, characterized by an increase in serum estradiol level
of 200 times above their normal value, roughly similar
to those of normal females, while those of testosterone
decreased by 90% relative to controls . ese changes in
tends to equalize parasite loads in females and males, which
suggests that other gonad-associated factors are involved in
the control of parasite growth. erefore, a more intricate
strategy of parasite activity has to be considered. Perhaps,
high estrogen levels are the main feature of this intriguing
puzzle, since, in males, the parasite loads increased more
markedly than in females. We suppose that expression of
costimulatory molecules early during infection could be
differential, and this fact impacts the parasite loads that are
hypothesis was tested in this study and found that always
L1, and PD-L2 during infection, but not in response to saline
or TcEx. Interestingly, estradiol concentrations are higher in
infected females early in infection .
the hormonal milieu of the host equalize the parasite loads
between genders. In the same way, progesterone treatment
In summary, the results presented here demonstrate that
recruitment and expression of MHC-II, CD80, CD86, PD-
L1, and PD-L2 in M𝜙𝜙 of peritoneal cavity in T. crassiceps
not differ between both sexes. Whatever the cysticercosis-
relevant “sex steroid target” may prove to be, the fact steroids
positively may interfere with the development of protective
immune mechanisms against Taenia crassiceps cysticerci has
an important implication for future vaccine and vaccination
trials, among others projections.
early at infection is associated to the sex of the host,
Financial support was obtained by Grant number IN214011
from Programa de Apoyo a Proyectos de Investigación e
Inovación Tecnológica (PAPIIT), of the Dirección Gen-
eral de Asuntos del Personal Académico (DGAPA), from
Universidad Nacional Autónoma de México (UNAM) to J.
Morales-Montor. C. Togno-Peirce had a Ph.D. fellowship
from CONACyT, México, and from UNAM. K. Nava-Castro
is a Postdoctoral Fellow from DGAPA, U.N.A.M.
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