MAJOR ARTICLE
Fc Receptor–Mediated Antibody Regulation of T Cell
Immunity against Intracellular Pathogens
Terri Moore,1 Charles O. Ekworomadu,1 Francis O. Eko,1 LuCinda MacMillan,1 Kiantra Ramey,1 Godwin A. Ananaba,1
John W. Patrickson,1 Periakaruppan R. Nagappan,1 Deborah Lyn,1 Carolyn M. Black,2 and Joseph U. Igietseme1,2
1
Morehouse School of Medicine and 2National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
Immunity to intracellular microbial pathogens, including Chlamydia species, is controlled primarily by cellmediated effector mechanisms, yet, the absence of antibodies results in inefficient microbial clearance. We
investigated the hypothesis that certain Fc receptor functions promote the rapid induction of elevated T helper
type 1 (Th1) response, which effectively clears chlamydiae. FcR⫺/⫺ mice exhibited a delayed and reduced
frequency of Chlamydia-specific Th1 cells, compared to FcR+/+ mice. In vitro, antichlamydial antibodies increased the rate of Th1 activation by FcR+/+ but not FcR⫺/⫺ antigen-presenting cells. FcR⫺/⫺ dendritic cells and
the T cell–associated IgG2A and IgA mediate enhanced Th1 activation by antibodies. Immunization with
chlamydia-antibody complexes induced elevated and protective Th1 response. These results provide a mechanistic basis for requiring both T cell and humoral immune responses in protective immunity and vaccine
evaluation. Findings offer a paradigm in host defense wherein different effector components function indirectly
to maximize the principal effector mechanism.
Designing vaccines against Chlamydia trachomatis require a better understanding of the elements of protective immunity. The current paradigm is that immunity is mediated primarily by a Th1 response [1–5];
however, a complementary role for certain less defined
B cell functions ensure an efficient microbial clearance,
especially during reinfections [2, 6]. Thus, a potentially
protective vaccine should elicit both T cell and humoral
immune responses, but the precise role of antibodies
has remained undefined. Among the antimicrobial
mechanisms of antibodies [7], binding and neutralization of infectious chlamydia particles is apparently
ineffective in vivo [8]. However, FcR-mediated effector
functions of antibodies, including antibody-dependent
cellular cytotoxicity (ADCC) and receptor-mediated
endocytosis leading to enhanced antigen presentation,
have a potential role in chlamydial immunity. Because
Received 29 January 2003; accepted 17 March 2003; electronically published
29 July 2003.
Financial support: National Institutes of Health (grants AI41231, GM 08248,
and RR03034 to P.H.S.); Centers for Disease Control and Prevention.
Reprints or correspondence: Dr. Joseph U. Igietseme, NCID/SRP/CDC, Mailstop
17, 1600 Clifton Rd, Atlanta, GA 30333 ([email protected]).
The Journal of Infectious Diseases 2003; 188:617–24
2003 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2003/18804-0020$15.00
there is limited ADCC against infected cells [9] and
immunity is specific to chlamydial serovars [10] and
effectors [3, 4], the role of antibodies in chlamydial
immunity may be indirect—perhaps to enhance Th1
development via rapid antigen uptake, processing and
activating specific Th1 cells. However, there is no
physiologic evidence that antibody enhancement of T
cell activation [11, 12] can be measured as a determinant of the efficacy of adaptive immunity against
pathogens.
It is known that FcR-mediated uptake concentrates
antigens in antigen-presenting cells (APCs), dramatically lowering T cell activating dose [13, 14], fostering
rapid delivery of endosomes to lysosomes for processing and loading of peptides on major histocompatibility
complex (MHC) molecules [15, 16], and facilitating an
adjuvant advantage of 100–1000 fold [11, 13, 15,
17–19], including cross-priming [12]. Also, dendritic
cells (DCs) are motile, highly potent primary APCs,
widely distributed in mucosal and other tissues [18,
20], expressing the endocytic receptors, FcRs, and mannose receptors, for uptake of immune complexes (ICs)
and glycosylated proteins, respectively [20, 21]. Most
DCs possess high costimulatory ability as a result of elevated density expression of costimulators, such as interleukin (IL)–1, IL-12, intercellular adhesion molecule
Antibody Regulation of T Cell Immunity • JID 2003:188 (15 August) • 617
1 (ICAM-1), leukocyte function antigen (LFA)–3, CD40, and B7
molecules [22–25]. The importance of DCs in antichlamydial
immunity [22, 26, 27] is the result of their ability to transport
antigen from the mucosal epithelium to the draining mucosal
inductive sites [20, 28, 29], their efficient processing and presentation of chlamydial antigens [24, 26, 27, 30], and their proclivity for activating Th1 response [23, 25]. We tested the hypothesis that a major role for antibodies in chlamydial immunity
is the enhancement of Th1 activation via FcR-mediated processes
involving DCs. By use of Fc receptor knockout (FcRKO) mice,
we demonstrated that specific antibodies and FcRs are crucial
for the development of an enhanced and effective Th1 response
during reinfections and that the process has significant clinical
implications.
MATERIALS AND METHODS
Chlamydia, animals, infection, and analysis of the course of
the infection. Stocks and antigens of C. trachomatis agent of
mouse pneumonitis (Chlamydia muridarum or MoPn) were
prepared by propagating elementary bodies in McCoy or HeLa
cells, as described elsewhere [31]. Female FcR⫺/⫺ on (C57BL/
6:129) background, lacking the activatory FcgRI (CD64) and
FcRgIII (CD16) and inhibitory FcgRIIB1 (CD32), were developed by gene targeting inactivation by Dr. Jeffrey Ravetch
(Memorial Sloan Kettering Cancer Institute, University of California, San Francisco). These animals and the wild-type (wt)
control FcR+/+ mice (aged 5-8 weeks) were obtained from Taconic Farms. Animals received food and water ad libitum and
were maintained in Laminar flow racks under specific pathogen–free conditions of 12 h light and 12 h darkness.
Mice were infected intravaginally with 105 inclusion-forming
units (IFUs) of MoPn per mouse in a volume of 30 mL of PBS
while under phenobarbitol anesthesia [32]. The course of the
infection was monitored by periodic cervicovaginal swabbing
of individual animals and isolation of Chlamydia in tissue culture, according to standard methods [31]. Groups of animals
were reinfected 85 days after the primary infection with 105
IFUs of MoPn per mouse and swabbed for isolation of chlamydiae and/or killed to determine the development of hydrosalpinx. For assessment of complication of hydrosalpinx, mice
were surgically dissected to expose the entire reproductive system. The uterine and oviductal regions were inspected for visible evidence of classic hydrosalpinx in infected mice. Experiments were repeated 2 times.
Measurement of frequency of mucosal and systemic chlamydial-specific Th1 cells (Th1 frequency) after a secondary
genital chlamydial infection of FcR5/5 and wt FcR+/+ mice.
A modified procedure for the limiting dilution technique [33,
34] was used. In brief, T cells were isolated from the iliac lymph
nodes (ILNs) and spleens of infected mice at the indicated times
618 • JID 2003:188 (15 August) • Moore et al.
Figure 1. Frequency of specific Th1 cells after a secondary genital
chlamydial infection of wild-type (wt) and Fc receptor knockout (FcRKO)
mice. A modified procedure of the limiting dilution technique [33] was
used to assess Th1 frequency in infected mice [33, 34]. T cells isolated
from the lymphoid tissues of infected mice at the indicated times and
cultures were established by seeding T cells in a serial doubling dilution
into 96-well round-bottom tissue culture plates, as described in Materials
and Methods. After incubation, the supernatants were assayed for interferon-g by a sensitive ELISA, and frequency of chlamydial-specific Th1
cells was calculated. T cells from naive mice have a Th1 frequency of
15 (range, 9–21) per 106 cells. ILNs, iliac lymph nodes.
and were seeded in a serial doubling dilution into 96-well
round-bottom tissue culture plates at 24 wells/dilution. The T
cells were stimulated with APCs from wt mice (2 ⫻ 10 5 cells/
well) and chlamydial antigen (10 mg/mL). Background cultures
contained 24 wells with APCs and antigen. After 5 days of
incubation, the supernatants were assayed for interferon (IFN)–
g by a sensitive ELISA [35]. The mean and SD of all 24 replicates
of background cultures were calculated. Three times the value
of the SD was added to the mean value, and the sum was the
baseline for positive experimental wells. After determination of
the number of positive and negative wells per dilution of each
T cell preparation, the data were analyzed by a limiting dilution
computer program (LIDIA) [33], which provided both the Th1
frequency and the conformity of the input data with a singlehit Poisson model. The data are expressed as Th1 frequency
per 106 responding T cells. T cells from naive wt mice have a
Th1 frequency of 15 (range, 9–21) per 106 cells.
Cytokines, antibodies, and other reagents. ELISA kits for
quantitating the amounts of murine cytokines in biological and
culture fluids were purchased from BioSource International.
Mouse anti–MoPn antibodies were prepared by 50% ammonium sulfate precipitation of gamma-globulin fraction of
hyperimmune sera from C57BL/6 mice infected multiple times
with MoPn by the genital route, as described elsewhere [31].
The presence of different antibody isotypes, including IgG2a,
IgG2b, and IgA, in the anti-MoPn antibody preparation, was
ascertained by ELISA [35]. High-titered mouse anti–Myco-
Figure 2. Kinetics of Th1 activation by wild-type (wt) and Fc receptor knockout (FcRKO) antigen-presenting cells (APCs) in the presence of
antichlamydial antibodies (left panel “A”). Purified cell preparations (T cells) were stimulated with splenic APCs from either FcR⫺/⫺ or FcR+/+ mice plus
chlamydial antigen, in the presence or absence of specific antichlamydial antibodies (anti-MoPn) or an irrelevant antibody preparation(anti–Mycobacterium
tuberculosis [anti-TB]), in tissue-culture plates for 1, 2, and 5 days. At the end of the incubation period, the supernatants were collected and assayed
for interferon (IFN)–g content by a quantitative sandwich ELISA [35]. The concentration of the cytokine in each sample (pg/mL) was obtained by
extrapolation from a standard calibration curve generated simultaneously. Data are mean SD values of triplicate cultures for each experiment and
are derived from at least 3 independent experiments. Control cultures containing T cells and APCs without chlamydial antigen showed no measurable
amounts of IFN-g; thus, the data are not shown. Also, cultures containing anti-TB antibodies did not show any measurable difference, compared with
cultures without anti–MoPn antibodies, as described elsewhere [9]; therefore, the results are excluded here. Kinetics of Th1 activation by wt and
FcRKO APCs in the presence of antichlamydial antibodies (left panel “B”). Shown is a reproduction of a segment of the results shown in left panel
(A), in which the data from cultures containing APCs, chlamydial antigen, and anti–MoPn antibodies (left panel “C”) are presented for clarity of the
comparison of the impact of FcRs on Th1 augmentation in the presence of antichlamydial antibodies.
bacterium tuberculosis (anti-TB) serum antibodies (prepared in
a similar manner) were provided by Dr. Ram Navalkar (Morehouse School of Medicine, Atlanta).
Immunohistochemistry. At the indicated time periods after a reinfection (i.e., days 7 and 28), mice were killed, and a
portion of the reproductive system between the cervix and the
ovaries of each mouse (i.e., the cervix, uterus, and fallopian
tubes) was excised and fixed in 10% formalin. The tissues were
transferred to 70% ethanol and were treated with sodium borohydride, to remove excess aldehydes that could obscure epitopes
and prevent antibody binding. Tissues were cut into 5-mm sections on a cryostat microtome, transferred onto slides, air dried,
and fixed in acetone. Sections were washed and stained with
primary monoclonal antibodies (MAbs) recognizing the indicated murine leukocytes antigens. Control sections were stained
with isotype-matched irrelevant antibodies. Mouse reactive
MAbs used were as follows: CD3␧ (clone 145–2C11), CD4
(clone H129.19), CD8 (clone 5H10–1), CCR3 (polyclonal), and
CCR5 (clone C34–3448). Binding of biotinylated species-specific antibodies was detected by streptavidin-peroxidase staining. Slides were viewed with Nikon Microphot Provia 400 daylight film. In some of the results, the percentage of positively
stained cells in the sections or the intensity of staining for each
leukocyte marker was determined by enumerating cells in 10
randomly chosen fields. In other results, the images were dig-
italized with a Polaroid SprintScan 35-mm slide scanner and
processed in Adobe Photoshop 5.0.
Effect of specific antichlamydial antibodies on chlamydial
antigen presentation for Th1 activation by APCs from FcR5/5
and FcR+/+ mice. To assess the effect of specific antichlamydial
antibodies on APCs from either FcRKOs or control mice,
2 ⫻ 10 5 splenic cells (or 1 ⫻ 10 4 bone marrow–derived DCs
[BMDCs]) were cocultured with 2 ⫻ 10 5 nylon-wool–purified
T cells in the presence or absence of chlamydial antigen (10
mg/mL) and specific anti–MoPn antibodies (50 mg/mL) in 96well tissue culture plates for 24, 48, and/or 120 h. Anti-isotype
antibodies (i.e., rabbit anti–mouse IgG1, IgG2a, IgG2b, IgG3,
and IgA) were used at 50 mg/mL in culture to determine the
antibody isotype or isotopes responsible for augmenting T cell
activation. Preliminary studies indicated that that there was no
significant difference between the effect of equivalent titers of
whole and F(ab)2 anti-isotype antibodies on the Th1 enhancement caused by anti–MoPn IgG2a or IgA in this culture system.
Therefore, the more readily available whole anti-isotype antibodies were used in the reported results. At the end of each
incubation period, the supernatants were collected and assayed
for IFN-g content by a quantitative ELISA [9]. The results were
derived from at least 3 independent experiments.
Induction of augmented protective Th1 response by chlamydia-antibody complexes. Four groups of mice were vacAntibody Regulation of T Cell Immunity • JID 2003:188 (15 August) • 619
Figure 3. Immunohistochemical localization of Th1 cells in the genital mucosa of infected wild-type (wt) and Fc receptor knockout (FcRKO) mice.
Genital tissue sections from reinfected wt and FcRKO mice were analyzed by immunocytochemistry for the murine chemokine receptor CCR5 expressed
on Th1 (CD4 and CD8) and dendritic cells by use of the biotin-streptavidin-peroxidase detection system. Slides were viewed with Nikon Microphot
Provia 400 daylight film. Images were digitalized with a Polaroid SprintScan 35-mm slide scanner and processed in Adobe Photoshop 5.0.
cinated 2 times by the intranasal route at 3-week intervals, as
follows. Group 1 received 107 IFUs ultraviolet (UV)–inactivated
MoPn in 30 mL of PBS; group 2 received 107 IFUs UV-inactivated MoPn mixed with anti–MoPn antibodies (1:100 titer);
group 3 received equivalent amounts of anti–MoPn antibodies
as group 2; and group 4 received 107 IFUs live MoPn. Two
weeks after the last immunization, the frequency of MoPnspecific Th1 cells in the ILNs were determined, as described
elsewhere [35]. Also, purified immune T cells were adoptively
transferred from vaccinated mice into naive mice, and the latter
were challenged with 104 live MoPn after 24 h [34]. Protective
adoptive immunity was measured by isolation of chlamydiae
from cervicovaginal swabs at 7 days after challenge, as described
elsewhere [31]. The results were collated as mean SEM of 2
independent experiments.
Statistical analysis. The levels of IFN-g in samples and
IFUs from different experiments were analyzed and compared
by performing a 1- or 2-tailed Student’s t test, and the relationship between different experimental groupings was assessed
by analysis of variance. Minimal statistical significance was
judged at P ! .05.
RESULTS
Frequency of specific Th1 cells after a secondary genital chlamydial infection of wt and FcRKO mice. We tested the hypothesis that the high intensity and delayed resolution of secondary genital chlamydial infection exhibited by FcRKO mice
620 • JID 2003:188 (15 August) • Moore et al.
[9] is the result of a slow rate and low Th1 activation during
reinfections. Results presented in figure 1 indicate that the frequency of mucosal Th1 induced by wt FcR+/+ mice was ∼6fold higher than that of FcR⫺/⫺ mice by the first week of infection. In addition, T cell response was elicited in the mucosal
and systemic lymphoid tissues in wt mice by the first week,
but systemic response increased further by ∼40% at week 4
after reinfection. On the other hand, a low Th1 response was
first detectable in the genital mucosal draining ILNs of FcRKO
mice by the first week, whereas systemic response was undetectable, suggesting that the local immune response preceded
the systemic response.
The systemic Th1 response in the FcRKO mice was detected
at the later time interval (4 weeks) at a level ∼5-fold less than
the systemic response of the wt mice. Thus, the induction of
Th1 response in FcRKO mice is delayed and suppressed, suggesting that an inadequate T cell response may be responsible
for the greater intensity of secondary infection in the mice [9].
Furthermore, when groups of reinfected wt and FcRKO animals
were evaluated for tubal complications, the incidence of hydrosalpinx formation was 1 in 10 infected wt mice, whereas all 10
FcRKO mice developed hydrosalpinx. The results indicated that
the delayed and low capacity to induce adequate Th1 response
allowed for increased ascending infection and consequently
high incidence of development of tubal complications.
Kinetics of Th1 activation by wt and FcRKO APCs in the
presence of antichlamydial antibodies. The presence of antichlamydial antibodies (anti–MoPn antibodies), antigen, and
by immunocytochemistry for the murine leukocytes antigens
CD3␧, CD4, CD8, CCR3, and CCR5 1 week after reinfection,
FcRKO mice contained ∼25% of the cells bearing CD3, CD4,
and CCR5 present in wt mice. However, equivalent proportions
of cells bearing CD8 and CCR5 were detected in the genital
tissues from wt and FcRKO mice, which suggests that FcRdeficiency affected the induction of CD4+, but not CD8+, Th1
cells. Figure 3 shows the digitalized images of the CCR5-stained
tissues from wt and FcRKO mice. The preponderance of CCR5positive cells, indicative of Th1 cells, such as CD4+ Th1, CD8+,
and DCs, in the wt mice, but the paucity or absence of these
cells in the FcRKO mice can be clearly observed. Therefore,
the greater disease and delayed clearance of secondary chlamydial infection in FcRKO mice is associated with the low
induction and recruitment of Th1 cells into the genital mucosa.
Role of DCs and specific antibody isotypes in FcR-mediated
enhanced Th1 activation.
Results presented in figure 4
(splenic APCs) and figure 5 (BMDCs) reveal that the presence
Figure 4. Role of specific antibody isotypes in FcR-mediated enhanced
Th1 activation. Splenic APCs were pulsed with either chlamydial antigen
alone or antigen plus antichlamydial antibodies (anti-MoPn) and used to
activate purified immune T cells in culture [9] and as described in Materials
and Methods. Anti–Mycobacterium tuberculosis (anti-TB) is an irrelevant
control for anti-MoPn. Equivalent cultures also contained blocking antibodies directed at different murine antibody isotypes to evaluate the role
of different isotypes on the anticipated response. At the end of the
incubation period, the supernatants were collected and assayed for interferon (IFN)–g content by a quantitative sandwich ELISA, as described
elsewhere [35]. The concentration of the cytokine in each sample (pg/
mL) was obtained by extrapolation from a standard calibration curve
generated simultaneously. Data are mean SD values of triplicate cultures for each experiment and are derived from at least 3 independent
experiments.
FcR-positive APCs resulted in a faster activation of Th1 cells
and ultimately a greater overall Th1 response as compared with
cultures containing FcRKO APCs, antigen and anti-MoPn, or
FcR-positive APCs plus antigen without anti–MoPn antibodies
(figure 2A). In fact, as more precisely depicted in figure 2B,
within 24 h of incubation, the presence of anti–MoPn antibodies caused an ∼5-fold increase in Th1 activation over cultures containing FcRKO APC plus anti–MoPn antibodies or
cultures without antibodies. The rapid Th1 response with 24
h in the presence of anti–MoPn antibodies approached the level
of a 5-day antigen plus wt APC culture. As reported elsewhere
[9], control cultures containing an irrelevant antibody preparation did not enhance T cell activation (data not shown). Thus,
specific antichlamydial antibodies and FcR-positive APCs lead
to a faster rate of Th1 activation against Chlamydia.
Immunohistochemical localization of Th1 cells in the genital mucosa of infected wt and FcRKO mice. When genital
mucosal tissue sections from wt and FcRKO mice were analyzed
Figure 5. Role of dendritic cells (DCs) in FcR-mediated enhanced Th1
activation. Bone marrow-derived DCs (BMDCs) were pulsed with either
chlamydial antigen alone or antigen plus antichlamydial antibodies (antiMoPn) and were used to activate purified immune T cells in culture, as
described in the legend to figure 2A and in Materials and Methods.
Equivalent cultures also contained blocking antibodies directed at different
murine antibody isotypes, to evaluate the role of different isotypes on
the anticipated response. At the end of the incubation period, the supernatants were collected and assayed for interferon (IFN)–g content by a
quantitative sandwich ELISA [35]. The concentration of the cytokine in
each sample (pg/mL) was obtained by extrapolation from a standard
calibration curve generated simultaneously. Data are mean SD values
of triplicate cultures for each experiment and are derived from at least
3 independent experiments.
Antibody Regulation of T Cell Immunity • JID 2003:188 (15 August) • 621
Table 1. FcR-mediated induction of high frequency of protective
Th1 cells.
Frequency of Th1 cells
per 106 cells (range)
Group
UV-MoPn only
UV-MoPn +
Anti-MoPn
Anti-MoPn only
b
50 (36–72)
1600 (1067–2133)
10 (7–13)
a
Protection
0/6 (6.1 ⫻ 104 1250)
9/10 (86 23)
0/6 (1.2 ⫻ 105 2280)
Live MoPn
2600 (1733–3467)
NOTE.
IFUs, inclusion-forming units; UV, ultraviolet.
10/10 (0)
a
Data are no. of negative/total no. of mice challenged (mean SEM in
IFUs/mL of total mice in each group). Protection was measured by IFUs of
chlamydiae recovered from cervicovaginal swabs and expressed as both the
number of mice that were resistant to infection out of the total mice
challenged.
b
Live MoPn delivered intranasally induces a potent genital mucosal Th1
response that is protective against genital chlamydial infection [35] and thus
was used as the positive control.
of antichlamydial antibodies increased Th1 activation, as demonstrated elsewhere for splenic APCs [9]. In addition, treatment
with antimurine Ig2a abrogated the T cell–enhancing effect of
antichlamydial antibodies in cultures of splenic APCs. However,
treatment with antimurine IgA only partially but significantly
(P 1 .002) reduced the effect, which suggests that Ig2a was more
effective in systemic Th1 augmentation than IgA. Furthermore,
treatment with antimurine IgA abrogated the T cell–enhancing
effect of antichlamydial antibodies in cultures of DCs, although
treatment with antimurine Ig2a also significantly (P 1 .007 ) reduced the effect, which suggests that IgA was more effective in
DCs (and possibly mucosal) Th1 augmentation than Ig2a.
Therefore, these data reveal that both splenic APCs (which
include macrophages and follicular DCs) and possibly mucosal
DCs are active mediators of FcR-dependent augmentation of
T cell response during chlamydial reinfections and that IgG2a
and IgA are important in the process.
FcR-mediated induction of high frequency of Th1 cells as
a vaccine strategy against chlamydia. Table 1 shows that
when groups of mice were vaccinated by the intranasal route
with UV-inactivated MoPn mixed with anti–MoPn antibodies,
the frequency of chlamydial-specific Th1 cells in the genital
mucosa-draining ILNs was 1600 Th1 cells per 106 ILNs (range,
1067–2133 per 106 cells). This response was 32-fold greater than
the Th1 frequency obtained with UV-inactivated MoPn alone
and was comparable to the response in mice that received live
MoPn (2600 Th1 cells per 106 ILNs; range, 1733–3467 per 106
ILNs), which was shown elsewhere to induced high levels of
protective Th1 response [35]. The induction of protective Th1
cells was verified by the ability of immune T cells from either
live-MoPn–exposed or UV-MoPn mixed with anti–MoPn antibodies to transfer protection against genital chlamydial infection (table 1). Thus, immunization with ICs comprising chlamydiae and specific antichlamydial antibodies was capable of
622 • JID 2003:188 (15 August) • Moore et al.
rapidly boosting high frequency of Th1 cells that conferred
protective immunity against chlamydia.
DISCUSSION
These studies reveal that antibodies participate in antichlamydial
immunity by facilitating rapid and elevated Th1 response via
FcR-mediated processes and that DCs may play a pivotal role in
Th1 augmentation during reinfections in vivo. FcR-mediated
enhancement of Th1 response is therefore a component of the
memory response that drives the induction of faster and higher
immune effectors that rapidly clear reinfections. In corroborating
reports, FcRKO mice were more susceptible to influenza infection, even in the presence of anti-influenza antibodies, a mechanism that was NK cell independent, although Th1 enhancement
was not investigated [36]. Delayed induction or inadequate Th1
response lead to ascending infection and complications of genital
chlamydial infection in animals [37] and humans [38]. A potential intervention strategy is the use of Th1 enhancers or immunomodulators in combination with antimicrobial therapy
[39–41], which requires establishing the optimum level of Th1
that mediates microbial clearance without pathology.
Only the cell-mediated immunity–associated IgG2a and IgA
could perform antibody enhancement of Th1 activation. Thus,
cross-linking the FcaR (CD89) on mucosal DCs caused cell
activation, which suggests a major role in antigen sampling and
presentation in mucosal epithelia for an enhanced T cell activation [42]. Mechanistically, FcR delivery of antigen increases
the antigen-capturing and internalization ability of APCs and
enhances both the antigen processing capacity and the T cell–
activating mode, leading to a rapid and augmented T cell response. IL-12 delivered by APCs is important for signaling
via signal transducers and activators of transcription type 4
(STAT4), which stimulates IFN-g gene expression and activation-induced differentiation of naive T cells to the Th1 phenotypes [43].
Therefore, a plausible mechanism for FcR-mediated acceleration of Th1 activation is rapid uptake of opsonized antigen,
followed by efficient processing in targeted intracellular endosomal and cytoplasmic compartments, involving stimulation
of proteosomal, lysosomal, or endosomal enzymes, and induction of transcription factors, such as STAT2 and STAT4, that
are associated with Th1 cell activation [44–46]. Thus, FcRmediated internalization enhances timely endosomal transport,
processing, and loading onto MHC molecules, which is dependent on induction of the cellular signaling and activation
system via the protein tyrosine kinase PTK syk [15]. FcR-mediated antigen uptake also promotes DC maturation and facilitates immune response different antigens [15]. Certain antibody isotypes may direct an antigen to a specific intracellular
environment that favors Th1 versus Th2 activation by prefer-
ential induction of certain transcription factors [21, 47], and
this targeted signaling may involve specific FcRs for IgG2a and
IgA. Finally, FcR-mediated delivery of antigen could potentially
constitute an effective vaccination strategy and an adjuvant for
boosting immune response against pathogens or tumors [48].
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