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*
Department of Molecular Genetics, Chiba University Graduate School of Medicine; and
First Department of Internal Medicine, Chiba University School of Medicine, Chiba, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-/- mice lacking the expression and
function of FcRI, FcRIII, and Fc
RI. We found that the
delayed-type hypersensitivity response in
FcR-/- mice is significantly decreased
compared with that in wild-type mice. Moreover, the secondary responses
of proliferation and cytokine production as well as the Ab formation by
CD4+ T cells from FcR-/- mice
to Ag and normal APCs were also reduced. In contrast, in vitro primary
T cell proliferative responses upon stimulation with anti-TCR Ab or
MLR as well as in vivo primary response against staphylococcus
enterotoxin B administration were not different between T cells from
FcR-/- and wild-type mice. In addition,
the Ag presentation function of APCs from unimmunized
FcR-/- mice was normal. On the other hand,
Ab-deficient mice also revealed impaired T cell responses. These
results demonstrate that the defective T cell responses in
FcR-/- mice were due to impaired Ag
presentation during in vivo priming not to a defect in T cells.
Therefore, they suggest that the FcRs on APCs mediate efficient priming
of Th cell responses in vivo in an immune complex-dependent
manner. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rs: a high affinity receptor, FcRI (CD64),
which is capable of high affinity-binding to monomeric IgG; and two low
affinity receptors, FcRII (CD32) and FcRIII (CD16), which exhibit
low affinity-binding to monomeric IgG and then bind mainly to polymeric
IgG. FcRI and FcRIII are composed of multimeric subunits and
require a homodimer of the subunit (FcR) for their assembly and
cell surface expression as well as for signal transduction through
FcR. The FcR chain is also associated with the high affinity FcR
complex for IgE (FcRI).
Previous work demonstrated that FcR-deficient (-/-) mice showed no
expression of FcRI, FcRIII, and FcRI on the surfaces of
various cells (3, 4). In addition, IgE-mediated
anaphylaxis by mast cells, which is a representative type I
inflammation, is impaired in
FcR-/- mice (3, 5). More importantly, it was shown that Arthus reaction induced
by immune complex
(IC)3 of specific Ag
and Ab, a representative type III inflammation, was severely reduced in
both FcR- and FcRIII-deficient mice (3, 6).
Furthermore, FcR-/-
mice failed to induce IgG-mediated phagocytosis by macrophages, and
they also exhibited severe reduction in the induction of
autoantibody-dependent experimental hemolytic anemia and
thrombocytopenia (7), anti-glomerular basement membrane
Ab-induced glomerulonephritis (4), and IC-induced
vasculitis syndrome (34). These results indicated that
FcRs play important roles in not only type I but also type II and
III inflammatory responses. However, it still remains unclear whether
FcR is also involved in a type IV inflammation. Regarding the type IV
response, the effects of the functions of FcRs on even normal T cell
functions have not been analyzed except for FcR-expressing
intestinal intraepithelial T cells (8) and
NK1.1+ T cells (9).
Dendritic cells (DCs) and macrophages are the major APCs in the immune
system and are involved in the activation and differentiation of
CD4+ and CD8+ T cells
(10, 11). Previously, it was reported that Ags
internalized through specific membrane receptors such as surface Ig and
FcRs are more efficiently presented to CD4+ T
cells compared with those internalized in the fluid phase in the case
of MHC class II-restricted presentation (12). Especially,
it is well known that FcRs are responsible for internalization of Ag by
forming ICs with specific Ab and facilitating efficient MHC class
II-restricted presentation in vitro. Similarly, FcRs also promote
efficient MHC class I-restricted presentation of peptides by
internalization of exogenous Ag-IgG ICs (13). FcRI and
FcRIII trigger activation signals through FcR, which bears an
immunoreceptor tyrosine-based activation motif (1, 14).
Indeed, signals from FcRs cause the maturation of DCs (13)
and promote efficient MHC class I and II-restricted Ag presentation.
However, the in vivo function of FcRs in MHC class I and II-restricted
Ag presentation to T cells is still poorly understood.
To clarify the role of FcR in type IV inflammatory responses and MHC
class II-restricted Ag presentation to CD4+ T
cells in vivo, we analyzed delayed-type hypersensitivity (DTH) and
proliferative responses of CD4+ T cells from
FcR-/- mice upon
stimulation with specific Ags. We found that the priming of
CD4+ T cells with a specific Ag is significantly
impaired in FcR-/-
mice in spite of the fact that the function of T cells from unimmunized
mice was normal. Together with the observation that the impaired T cell
responses were also observed in Ig-deficient mice, these observations
suggest that FcRs expressed on APCs play an important role in the
priming of Th cell responses in vivo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 and BALB/c mice were purchased from the Shizuoka Animal
Center (Hamamatsu, Japan). The establishment and characteristics of
FcR-/- mice with
C57BL/6 background have been described previously (4).
Membrane IgM-deficient mice (µMT) mice were produced as described
previously (15) and were provided by Dr. D. Kitamura
(Tokyo Science University, Chiba, Japan). All mice were bred and
maintained in our own animal facility under specific pathogen-free
conditions.
Delayed-type hypersensitivity
To measure DTH responses, we examined the swelling responses of footpads in mice. The basic protocol of the swelling assay was described previously (16). Briefly, mice were immunized by s.c. injecting 200 µl emulsion of CFA containing 200 µg of KLH at three sites, one on each flank and the third at the base of the tail. Two weeks or 10 wk after sensitization, 100 µg of keyhole lympet hemocyanin (KLH) in 20 µl of PBS was injected into the right footpad, and 20 µl of PBS was injected into the left footpad as a control. After 24 h, footpad swelling was measured (in mm) with a micrometer as [(right footpad thickness after challenge - right footpad thickness before challenge) - (left footpad thickness after challenge - left footpad thickness before challenge)].
Proliferative response of T cells
Mice were immunized with 200 µg of KLH or OVA with CFA
intradermally in both flanks and at the base of the tail for analysis
of splenocytes. Similarly, mice were immunized with 200 µg of KLH
with CFA intradermally in both fore and hind footpads for analysis of
lymph node cells. Three each of spleen or popliteal and axillary
draining lymph nodes from immunized mice were obtained 1, 2, 4, or 6 wk
after immunization. Splenocytes and lymph node cells were mixed with
anti-CD8 mAb (53.6.7) and incubated with magnet beads (Advanced
Magnetics, Cambridge, MA) coupled with goat anti-mouse IgG Ab and
goat anti-rat IgG Ab to remove surface Ig+ B
cells and CD8+ T cells. For the proliferative
response of splenocytes in wild-type,
FcR-/-, and µMT
mice, CD4+ T cells were purified by using MACS
(Miltenyi Biotec, Bergisch Gladbach, Germany) 3 wk after immunization.
The respective purities were 94, 96, and 93%. The cells were cultured
in 96-well U-bottom microplates (Falcon; Becton Dickinson, Mountain
View, CA) in the absence or presence of graded concentrations of KLH,
purified protein derivative (PPD), or OVA at 37°C in 5%
CO2 for 4 days, pulsed with 0.5 µCi of
[3H]thymidine for 8 h, and harvested on
glass filters. The incorporated radioactivity was measured with a
MicroBeta liquid scintillation counter (Wallac, Gaithersburg, MD). The
results of the [3H]thymidine incorporation
assay were expressed as the mean cpm ± SD of triplicate cultures
from each group of mice.
Titration of anti-KLH Abs in serum
Serum Ab titers were measured by modification of an ELISA assay. A 96-well microplate was coated with 50 µl/well of a 50 µg/ml solution of KLH in 0.1 M NaHCO3 at 4°C overnight and then was blocked with 50 µl/well of PBS containing 3% BSA at room temperature for 3 h. Serum was added at 50 µl/well and allowed to react at room temperature for 3 h. The wells were washed five times with PBS containing 0.05% Tween 20 and incubated with 50 µl of anti-mouse IgM, IgG1, IgG2a, IgG2b, or IgG3 coupled to HRP at room temperature for 1 h. Thereafter, plates were washed six times with PBS containing 0.05% Tween 20 before incubation at room temperature for 20 min with o-phenylenediamine as a substrate (Wako, Osaka, Japan).
Measurement of cytokine production
Culture supernatants were removed from wells after 72 h of
culture, and the concentrations of IL-2, IL-4, and IFN- were
measured by ELISA by standard protocol as described previously
(17). For analyzing the function of Ag presentation, IL-2
production from a T cell hybridoma was measured. An OVA-specific murine
T cell hybridoma, DO11.10, was cultured with irradiated splenocytes
from wild-type and
FcR-/- mice with
BALB/c background in the presence of various concentrations of
OVA peptide 323–339 and soluble OVA (18). Culture
supernatants were collected from wells after 24 h of culture, and
the concentration of IL-2 was measured by ELISA and by means of the
proliferation of IL-2-dependent cell line CTLL-2.
Flow cytometric analysis
Mice were given one i.v. injection of 50 µg of staphylococcus enterotoxin B (SEB) in 0.25 ml PBS. Two days later, peripheral blood cell suspensions were treated with NH4Cl to lyse RBC. These cells were washed and then incubated with F23.1 culture supernatant. The cells were then treated with biotinylated anti-mouse Ig for 40 min on ice and then with PE anti-CD4, FITC anti-CD8, and Quantum Red streptavidine for 40 min. After washing, cells were analyzed on a FACSCalibur (Becton Dickinson) using Cell Quest software.
Statistical Analysis
Statistical differences in each group for the DTH response, T cell proliferation, the levels of cytokines, and serum levels of Abs were calculated using Student’s t test or Welch’s t test. A p value <0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-/- mice
We first immunized wild-type and
FcR-/- mice s.c. with
KLH in CFA, and footpad swelling was measured upon challenging with Ag
at 2 and 10 wk after immunization to examine the contribution of FcRs
in the DTH response. As shown in Fig. 1
,
the DTH response in
FcR-/- mice was very
low compared with that in wild-type mice regardless of the
sensitization period, clearly indicating that FcR is involved in DTH
response.
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-/- and
wild-type mice after immunization with Ag, we analyzed the in
vitro secondary proliferative responses of purified
CD4+ T cells from immunized
FcR-/- and wild-type
mice upon stimulation with the Ag and irradiated splenocytes from
wild-type mice. As shown in Fig. 2,
A and B, proliferative responses of
CD4+ T cells from KLH-immunized
FcR-/- mice were very
low upon stimulation with both KLH and PPD in comparison with those
from wild-type mice. The response to PPD was raised due to the use of
CFA for immunization. Similar results were obtained when OVA was used
as Ag (Fig. 2C). Reduced proliferation of
CD4+ T cells from
FcR-/- mice was also
observed upon immunization with KLH in IFA (data not shown).
Furthermore, CD4+ T cells from draining lymph
nodes (LNs) of FcR-/-
mice also exhibited low proliferation upon immunization with KLH in CFA
(Fig. 2D).
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-/- mice
We compared the effect of the time course of priming of
CD4+ T cells on the proliferative responses
between wild-type and
FcR-/- mice.
Splenocytes were obtained from mice 1, 2, and 4 wk after immunization
with KLH, and CD4+ splenic T cells were
stimulated in vitro with KLH in the presence of wild-type APCs
(Fig. 3A). Regardless of the
duration of immunization, the proliferative responses by T cells from
FcR-/- mice were
significantly lower than those of wild-type mice. Although the
proliferative response decreased with time after immunization, the
ratio of the proliferation of CD4+ T cells from
wild-type mice to that from
FcR-/- mice
increased.
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-/- mice were
immunized with various doses of KLH, and CD4+ LN
T cells were assessed for proliferation 10 days later. As shown in Fig. 3
B, CD4+ T cells from
FcR-/- mice exhibited
lower responses with all Ag doses used. Although the proliferation of
CD4+ T cells decreased at lower doses of Ags, the
ratio of the proliferation of CD4+ T cells from
wild-type mice to that from
FcR-/- mice
increased.
Collectively, these results suggest that the efficiency of Ag
presentation to CD4+ T cells for
proliferation increases in the pres-ence of FcR in vivo,
particularly under the condition of low doses of Ag and longer periods
after immunization.
Suppression of Th cell-mediated cytokine and Ab production in
FcR-/- mice
Because DTH and proliferation were impaired in
FcR-/- mice, we
examined other Th cell functions such as cytokine production and
Ag-specific Ab formation. Defects in IL-2 and IFN- production by
CD4+ T cells from
FcR-/- mice were also
observed, which were well correlated with the impaired proliferative
response, although IL-4 production was below detection in both mice
(Fig. 3C).
We also measured the titers of anti-KLH Abs in sera after
immunization of wild-type and
FcR-/- mice with KLH.
Sera were obtained 2 wk after immunization, and the relative titers of
anti-KLH Abs were determined by ELISA. As shown in Fig. 4A, the relative
concentrations of anti-KLH Abs of all isotypes except for IgM were
low in FcR-/- mice
compared with wild-type mice. In contrast, there was no difference in
total Ig levels of any isotypes in sera between wild-type and
FcR-/- mice (Fig. 4B).
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is important not only for the
priming of T cells but also for the production of Ag-specific IgG
Ab.
Normal primary T cell responses and Ag presentation in
FcR-/- mice
The impaired T cell responses in
FcR-/- mice could be
attributed to a defect in either T cell function or Ag presentation. To
clarify the basis for this, we first analyzed the T cell function in
FcR-/- mice.
Because T cell functions in
FcR-/- mice have not
been analyzed previously except for intestinal intraepithelial T cells
(8) and NK1.1+ T cells
(9), both of which express FcR within the TCR complex,
we examined the in vitro primary T cell responses upon stimulation by
crosslinking with anti-TCRß mAb and anti-CD28 mAb,
superantigen (SAg), and MLR. As shown in Fig. 5, proliferative responses of
CD4+ T cells from
FcR-/- mice upon
stimulation with immobilized anti-TCRß mAb and anti-CD28 mAb
(Fig. 5A) as well as SAg SEB in the presence of normal APCs
(Fig. 5B) were almost the same as those of
CD4+ T cells from wild-type mice. The low
response to SEB was probably due to the C57BL/6 background of these
mice. Furthermore, MLR by CD4+ T cells from
FcR-/- mice did not
differ from those of normal mice (Fig. 5C). In addition, we
investigated the in vivo responses to SEB to address the
question of whether the in vivo primary T cell response to SAg in
FcR-/- mice is
impaired, to compare with the impaired secondary response to nominal
Ag. It has been shown that in vivo administration of SEB induces strong
proliferation of Vß8+ T cells and then a
decrease of these cells due to apoptosis (19). We followed
this protocol by administering SEB i.v. and analyzing the proportion of
Vß8+ T cells in spleen 2 days later. As shown
in Fig. 5D, the induction of proliferation at the initial
phase was almost the same for T cells from both
FcR-/- and
wild-type mice.
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-/- mice are normal
and therefore suggest that impaired T cell responses of DTH,
proliferation, and cytokine production upon immunization with Ag are
not due to any T cell defect but rather can be attributed to
inefficient priming upon secondary stimulation.
Because T cell function from
FcR-/- mice was not
impaired, we then investigated the function of Ag presentation to T
cells by APCs from
FcR-/- mice in vitro.
OVA-specific murine T cell hybridoma DO11.10 was cultured with
irradiated splenocytes from wild-type and
FcR-/- mice in the
presence of OVA peptide 323–339 (Fig. 6A) or whole OVA (Fig. 6B), and IL-2 secretion was assessed. The IL-2 production
from the hybridoma cocultured with APCs from
FcR-/- mice was almost
equivalent to that from wild-type mice irrespective of the requirement
of Ag processing. These results reveal that there is no difference in
APC function between
FcR-/- and
wild-type mice.
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-/- mice
It has been previously reported that IC composed of Ag and
specific IgG Ab was efficiently taken up via FcR-mediated endocytosis
by APCs such as DCs and macrophages, resulting in efficient Ag
presentation to CD4+ T cells in vitro
(20, 21, 22). Therefore, the reduction of T cell responses due
to impaired priming in
FcR-/- mice could be
attributed to the failure of IC-mediated triggering of FcR or to a
defect of unknown IC-independent function of FcR in Ag
presentation.
To investigate whether in vivo low responses of
CD4+ T cells from
FcR-/- mice were due
to a defect of FcR-mediated endocytosis of IC, we analyzed the
Ag-specific response of CD4+ T cells from µMT
mice in which B cell development has been shown to be severely impaired
and the level of Abs was extremely low (15). µMT mice
were immunized with KLH, and the proliferative response of
CD4+ splenic T cells was analyzed in vitro upon
stimulation with KLH in the presence of wild-type APCs. As shown in
Fig. 7A, the proliferative
response of CD4+ T cells from µMT mice was also
impaired as compared with that from wild-type mice, and it was almost
equivalent to that of
FcR-/- mice.
Furthermore, we observed that µMT mice exhibited reduced DTH response
(data not shown). On the other hand, there was no significant
difference in proliferative response by stimulation with PMA/A23187
among T cells from
FcR-/-, wild-type, and
µMT mice (Fig. 7B). These results suggest that IC and FcR
play an important role in the effective Ag presentation to
CD4+ T cells in an Ab-dependent manner in
vivo.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-/- mice and
demonstrated that the in vivo DTH response was clearly impaired in
FcR-/- mice. This
impaired response was seen not only in DTH but also in many other Th
cell functions such as T cell proliferation, cytokine production, and
Ab production as secondary responses. These impaired T cell responses
could be attributed to a defect either in T cells or in the Ag
presentation to T cells, and our analysis points to the latter.
We first analyzed the function of FcR in T cells, which has not yet
been analyzed extensively. The FcR transcript is not detectable in
the normal T cell population even by RT-PCR (our unpublished
observation). In this study, we showed that T cell responses in
FcR-/- mice upon
stimulation by TCR crosslinking, MLR, and SAg were not different from
those of normal T cells. In addition, the in vivo primary response to
SAg was not impaired either. Collectively, it can be concluded that
primary T cell responses by
FcR-/- T cells are
normal. This is consistent with the previous result that T cell
development was not impaired in
FcR-/- mice (1, 3). Therefore, the observed defect in various responses by
CD4+ T cells in
FcR-/- mice cannot be
attributed to a defect in T cells.
An alternative possibility for the observed impairment in DTH and
proliferation of CD4+ T cells in
FcR-/- mice may be a
defect in APC function, because APCs such as macrophages and DCs
express FcR and FcR (3, 4, 13, 23). It has been
previously reported that APCs including DCs and macrophages are able to
present Ags with 100-fold higher efficiency in the presence of Ag-Ab
IC. This is because IC was taken up more efficiently via FcR-mediated
endocytosis by APCs than by Ag alone, resulting in an efficient Ag
presentation to CD4+ T cells in vitro
(20, 21, 22, 24, 25). A defect in FcR-dependent enhancement of
Ag presentation to CD4+ T cells may lead to a low
response of T cells in
FcR-/- mice in vivo.
The enhancement of Ab responses has recently been demonstrated by the
in vivo administration of in vitro preformed Ag-Ab ICs
(26). However, because such a system with artificially
preformed ICs does not reflect the physiological condition of the Ab
response after immunization with Ag, the function of naturally formed
IC under physiological condition has not been analyzed. In our study,
we demonstrated for the first time that
FcR-/- and
Ab-deficient mice exhibit suppression of Th cell responses and Ab
production under the condition of a physiological immunization
process.
Furthermore, our results revealed a decrease in the Ag-specific
proliferative responses of CD4+ T cells in µMT
mice. Previously, Epstein et al. (27) reported that T
cells in µMT mice exhibited normal functions in allo-responses.
Similar to T cell responses in
FcR-/- mice, it is
likely that primary T cell responses are normal, whereas secondary
responses are suppressed in µMT mice. Because ICs cannot be formed in
µMT mice, these results suggest that IC-mediated Ag presentation is
required for effective priming of CD4+ T cells.
This was further supported by the observation that APCs from
FcR-/- and wild-type
mice could equally stimulate in vitro T cell clones in which no
specific Ab was present. However, we cannot exclude the possibility
that APC function was reduced in the absence of B cells in vivo, which
µMT mice lack completely, although B cells are less effective APCs
than DCs or macrophages.
The present analysis demonstrated for the first time that FcR plays an
important role in augmenting the Ag-presenting capacity of DC or
macrophages through an IC-dependent mechanism in vivo, even though this
has already been assumed to be the case from in vitro studies.
Preliminary results showing that even when macrophages or DCs were
isolated from FcR-/-
mice, these cells did not exhibit any difference in T cell
proliferation, suggested that Ag presentation is augmented only in the
presence of ICs. Our data showing that T cells from
FcR-/- mice immunized
1 wk before readily exhibited a decrease in the response suggest that
functional ICs could be formed during such an early period. In
addition, we showed that the ratio of the proliferative response from
wild-type mice to that from
FcR-/- mice increased
with time and lower Ag dose. These results suggest that the interaction
of a low level of IC with FcR may affect the generation of memory
responses in vivo. Our observation that FcR augments secondary T cell
responses but not primary responses is also supported by the strong
suppression of IgG response but not IgM production in
FcR-/- mice. Because
the helper function of CD4+ T cells is required
for Ag-specific IgG but not IgM production, the failure of efficient
priming of CD4+ T cells is responsible for the
low level of Ag-specific IgG in
FcR-/- mice.
Considering that FcRI, FcRIII, and FcRI are not expressed on
the cell surface of various cells in
FcR-/- mice (3, 4), it is likely that FcRI and/or FcRIII are responsible
for effective Ag presentation in vivo. This is consistent with the
observations that human FcRI enhanced Ag presentation to T cells in
vitro (28, 29) and that Ab production was augmented in
transgenic mice expressing human FcRI (30). It has been
shown that crosslinking of FcRIIB together with B cell receptor
(FcRI) inhibits the activation of B cells (mast cells)
(31, 32, 33). Whether IC also inhibits the efficiency of Ag
presentation through FcRIIB is not yet known and has to be studied.
Because it still remains unclear which FcR contributes to efficient
presentation, further analysis using knockout mice for FcRI,
FcRIIB, and FcRIII on Ag presentation in our system might uncover
a pivotal function of FcR in the immune system.
As immunization progresses and specific Abs are produced, both
augmentation through FcRI/III and inhibition through FcRIIB may
occur. Thus, the total regulatory balance between such augmentation and
suppression remains to be investigated to reach a better understanding
of the physiological dynamics of immune responses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Takashi Saito, Department of Molecular Genetics, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
3 Abbreviations used in this paper: IC, immune complex; DC, dendritic cell; DTH, delayed-type hypersensitivity; KLH, keyhole lympet hemocyanin; PPD, purified protein derivative; SEB, staphylococcus enterotoxin B; LN, lymph node; SAg, superantigen; µMT, membrane IgM-deficient mice.
Received for publication January 14, 2000. Accepted for publication March 23, 2000.
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A. Getahun, J. Dahlstrom, S. Wernersson, and B. Heyman IgG2a-Mediated Enhancement of Antibody and T Cell Responses and Its Relation to Inhibitory and Activating Fc{gamma} Receptors J. Immunol., May 1, 2004; 172(9): 5269 - 5276. [Abstract] [Full Text] [PDF]
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S. L. Lambert, C. Y. Okada, and R. Levy TCR Vaccines against a Murine T Cell Lymphoma: A Primary Role for Antibodies of the IgG2c Class in Tumor Protection J. Immunol., January 15, 2004; 172(2): 929 - 936. [Abstract] [Full Text] [PDF]
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K. M. Dhodapkar, J. Krasovsky, B. Williamson, and M. V. Dhodapk |
). A and B, Proliferative responses
of splenic T cells to KLH. Four weeks after immunization with KLH in
CFA, splenic CD4+ T cells (3 x 105/well)
were purified and stimulated in vitro with various concentrations of
KLH (A) and PPD (B) for 4 days, and
proliferative responses were measured. Data are representative of nine
independent experiments. C, Proliferative responses of
splenic T cells to OVA. Four weeks after immunization, purified
splenocytes (3 x 105/well) were stimulated with OVA
for 4 days. Data are representative of two independent experiments.
D, Proliferative responses of LN T cells to KLH. Six
weeks after immunization, purified draining LN cells (3 x
105/well) were stimulated with KLH for 4 days. Data are the
representative of three independent experiments. The results are shown
as the mean of three mice ± SD. **, p <
0.01; *, p < 0.05; compared with wild-type
mice.
) and wild-type (WT) mice
(
). A, Effect of duration of Ag priming. Splenic
CD4+ T cells (3 x 105/well) were purified
and stimulated in vitro 1, 2, and 4 wk after immunization with 100
µg/ml of KLH for 4 days, and proliferative responses were measured.
The results are shown as the means of three mice ± SD. Ratios of
proliferation (cpm) of splenic T cells from wild-type to that from
FcR
, Fifty micrograms SEB primed; 
