| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Pediatrics, Stanford University, Stanford, CA 94305
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The experiments described here were undertaken to determine whether CD4+ T cells from JHD mice could be primed normally in vivo and whether such T cells were capable of providing help for B cells. We show that when rigorously purified, primed CD4+ T cells from JHD and normal BALB/c mice are compared, there is no difference in their proliferative responses to Ag. However, we also found that JHD T cells provided little or no help for Ab production. Additionally, we discovered that JHD T cells produce less IL-4 than normal T cells when B cells, but not splenic adherent cells (SpAC), are used as APCs, suggesting that the defect in providing B cell help may be due in part to a failure to up-regulate IL-4 synthesis in response to B cells.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
MD4 mice transgenic for hen egg lysozyme (HEL)-specific IgM and
IgD expressed in B cells (10) were backcrossed to BALB/cBy (11). After
seven generations, mice that screened positive for I-E
d
were selected and interbred. BALB/cByJ mice were obtained from either
The Jackson Laboratory (Bar Harbor, ME) or the Stanford Medical Center
Division of Laboratory Animal Medicine (Stanford, CA). B cell-deficient
JHD mice (5) were obtained from Dr. D. Huszar (GenPharm International,
Mountain View, CA) and were backcrossed to BALB/cBy for seven
generations. JHD mice were maintained on 1% Sulfatrim pediatric
suspension (Butler Co., Hayward, CA) for 4 days/wk. Homozygous B
cell-deficient mice were generated by interbreeding and identified by
PCR specific for the JH region (12). Animals were used
between 8 and 16 wk of age and were age and sex matched within each
experiment. All animal protocols were approved by the Stanford
University committee on animal welfare.
Antigens
HEL, OVA, BSA, and conalbumin were obtained from Sigma Chemical Co. (St. Louis, MO). OVA (Sigma lot 54F-8150) was found by ELISA and SDS-PAGE to be free of contaminating HEL. An HEL-OVA conjugate was prepared as previously described (11). KLH was purchased from Calbiochem (La Jolla, CA). TNP-coupled BSA, KLH, and conalbumin were prepared as previously described (13). Briefly, the protein of interest was dissolved in borate-buffered saline and reacted with trinitrobenzenesulfonic acid (ICN, Cleveland, OH) at a ratio of 38 mg trinitrobenzenesulfonic acid/g of protein, followed by extensive dialysis.
Immunizations
To generate OVA-primed CD4+ T cells, mice were immunized with OVA (200 µg/mouse) in CFA (Difco Laboratories, Detroit, MI) in the footpads. Draining popliteal, inguinal, and axillary LNs were removed 8 days after immunization. To generate KLH-primed Th cells, mice were immunized with KLH (150 µg/mouse) in CFA i.p., and spleens were removed 7 to 9 days later. For TNP-primed B cells, mice were immunized with 300 µg of TNP-conalbumin in CFA i.p., and spleens were harvested 3 to 4 wk later. In some experiments, mice were boosted at 4 wk with 300 µg of TNP-conalbumin in PBS and used 2 wk later. B cells from boosted and unboosted mice produced similar levels of Ab.
Medium
Cells were cultured in DMEM (Life Technologies, Grand Island, NY), supplemented as previously described (14) and containing 10% FCS (HyClone Laboratories, Logan, UT).
LN cell purification
In some experiments, LN cells were depleted of most B cells by passage over goat anti-mouse IgG- and IgM-coated (Jackson ImmunoResearch, West Grove, PA) plates as previously described (15). This was performed so that the number of T cells in the cultures from normal and JHD LNs would be roughly equivalent. No cells from the JHD mice bound to such plates.
T cell purification
Highly purified CD4+ T cells from LNs or spleens of OVA- or KLH-primed mice were prepared as previously described (16). Briefly, cells were passed over goat anti-mouse IgG- and IgM-coated (Jackson ImmunoResearch Laboratories) plates followed by two treatments with Abs against MHC class II, CD8, and heat-stable Ag plus baby rabbit C (Pel-Freez, Brown Deer, WI). T cells purified in this way failed to proliferate in response to Ag or Con A (Sigma Chemical Co.) in the absence of added APCs.
Preparation of SpAC
SpAC were prepared by adhering spleen cells from BALB/c By mice on plastic tissue culture dishes as previously described (11). The resulting cells were irradiated at 2500 rad before addition to cultures with T cells.
Preparation of Tg B cells
Purified B cells from MD4+/- Ig receptor transgenic mice were prepared as previously described (11). Briefly, spleen cells were allowed to adhere to plastic tissue culture dishes, and nonadherent cells were removed and treated with anti-Thy-1, anti-Mac-1, and mitomycin C (Sigma Chemical Co.). B cells prepared in this way were routinely 80% B220+ as determined by FACS.
Preparation of TNP primed B cells
Spleen cells from TNP-conalbumin primed mice were adhered to goat anti-mouse Ig-coated plates (15). Nonadherent cells were washed off, and the plates were incubated with warm PBS and 2% FCS for 5 min at 37°C. B cells were recovered by washing off with a stream of warm PBS and 2% FCS.
Proliferation assays
CD4+ T cells (2.7 x 106 cells/ml) were cultured in 96-well plates in 150 µl of medium in triplicate in the presence of a range of concentrations of either OVA or HEL-OVA. Either SpAC (2.7 x 105/ml) or B cells (2.7 x 105 or 3.3 x 106/ml) were added as APCs. Wells to which no APCs were added were used to control for T cell purity. After 72 h, cells were pulsed with 1 µCi of [3H]thymidine for 18 to 22 h. Cultures were harvested with a PHD harvester (Cambridge Technology, Cambridge, MA), and [3H]thymidine incorporation was measured using standard liquid scintillation counting techniques.
LN cell proliferation
To compare the proliferation of unfractionated LN cells from normal and JHD mice, LN cells were passed over goat anti-mouse Ig-coated plates, and the remaining LN cells were plated at 2.7 x 106/ml in 150 µl of medium in 96-well plates. Cultures were pulsed with [3H]thymidine after 72 h and harvested 18 to 22 h later.
Induction of lymphokine production by LN cells
After passage over goat anti-mouse Ig-coated plates, LN cells (2.7 x 106/ml) were cultured in replicates of six in 150 µl of medium with a range of concentrations of OVA. After 96 h, supernatants were harvested, pooled, and analyzed for cytokine content.
Induction of lymphokine production in primed CD4+T cells
CD4+ cells (2.7 x 106/ml)
were cultured in 24-well plates in 1 ml of medium in the presence of a
range of concentrations of either OVA or HEL-OVA. Either SpAC (2.7
x 105/ml) or B cells (2.7 x 105/ml) were
added as APCs. In some experiments, supernatants were harvested after
96 h. In other experiments, the cells were removed from the plates
after 96 h, washed once with PBS and 2% FCS, counted, resuspended
to 1.35 x 106/ml, and restimulated with fresh Ag and
APCs at concentrations identical with those used in the primary
stimulation. This restimulation was performed to optimize the
production of IL-4 (17). Supernatants were harvested 24 h after
restimulation and analyzed for cytokine content. Parallel cultures
containing T cells with Ag but no APCs produced negligible IL-4 or
IFN-
.
Help assays
TNP-primed B cells (3.3 x 106/ml) and KLH-primed T cells (1 x 106/ml) were cultured in 1 ml of medium in 24-well plates with a range of concentrations of TNP-KLH. Supernatants were harvested after 8 days and assayed for TNP-specific IgG. Wells containing T cells with no added B cells or B cells without T cells produced no detectable Ab.
Cytokine ELISAs
IL-4 and IFN- were assayed by ELISA as previously described
(11). The limits of detection were 7.8 pg/ml for IL-4 and 300 pg/ml for
IFN-. IL-5 was assayed using the same protocol, except that plates
were coated with 1 µg/ml anti-IL-5 mAb TRFK-5 (Dr. T. Mosmann,
University of Alberta, Edmonton, Canada) and biotinylated anti-IL-5
mAb TRFK-4 (Dr. T. Mosmann, University of Alberta) was used as the
second Ab. Supernatant from TH2 clone D10 that had been standardized
against recombinant murine IL-5 (Genetics Institute, Cambridge, MA) was
used as a standard, and the limit of detection was 780 pg/ml.
TNP-IgG ELISA
Ninety-six-well plates were coated with 5 µg/ml of TNP-BSA in bicarbonate buffer at 4°C overnight. After blocking for 1 h with PBS and 0.5% BSA, samples and standards were added and incubated overnight at 4°C. Plates were then incubated for 2 h at room temperature with horseradish peroxidase-labeled anti-murine IgG (Southern Biotechnology Associates, Birmingham, AL). Finally, plates were developed with O-phenyl-diamine (Sigma Chemical Co.) for 5 to 20 min, stopped with 2 N H2SO4, and read at 492 nm. Affinity-purified TNP-specific ascites from a TNP-BSA-hyperimmunized mouse was quantified for IgG by ELISA and used as a standard (18). The limit of detection was 1.95 ng/ml.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Whether T cells from B cell-deficient mice can be primed with Ag
is controversial. To address this question, we primed JHD or normal
BALB/c mice with OVA in CFA. Eight days later, the cells from the
draining LNs were examined. In normal mice, B cells constitute 50 to
60% of mononuclear cells in the spleen. Therefore, it was necessary to
normalize the number of T cells obtained from JHD and BALB/c primed
LNs. This was accomplished by passing the LN cells over
anti-Ig-coated plates, which depleted the majority of B cells.
Figure 1
A shows that primed
JHD LN cells proliferated poorly in response to Ag compared with primed
normal BALB/c LN cells. In addition, primed JHD LN cells secreted much
less IL-4 and IFN- compared with primed normal LN cells (Fig. 1, B and C).
|
The reduced proliferative response of LN cells from JHD mice was
not due to a lack of APC activity in these cultures, since removal of
the B cells leaves sufficient numbers of non-B cell APCs. Rather, we
hypothesized that the presence of primed B cells in the BALB/c LN
cultures greatly enhanced the responses of the BALB/c T cells and
falsely exaggerated the difference between BALB/c and JHD responses.
Therefore, highly purified CD4+ T cells were prepared
by passage over goat anti-mouse Ig-coated plates followed by two
treatments with Abs against MHC class II, CD8, and heat-stable Ag plus
complement. This treatment resulted in T cells that were completely
unresponsive to Ag or to Con A in the absence of added APCs. Figure 2A shows that the
proliferative response of primed CD4+ T cells from JHD mice
was equal to that of BALB/c T cells when stimulated with Ag presented
by SpAC, which consist of macrophages and dendritic cells. Cytokine
responses were also examined in cultures with CD4+ T cells
plus SpAC. We found that purified JHD and normal BALB/c T cells
secreted similar levels of IL-4 and IFN- (Fig. 2, C and
D). Figure 2B shows the response of LN
cells from the same mice before purification, demonstrating that, as in
Figure 1
, proliferation was greater in the LN cultures from normal
mice, which contained primed B cells. Primed B cells could enhance the
total proliferative response by proliferating themselves, by
stimulating increased T cell proliferation, or by carrying over Ag from
in vivo, as suggested by the higher proliferation in normal compared
with JHD LN cultures when no Ag was added (Fig. 2B).
|
To determine whether Ag-primed T cells from JHD mice were
effective in inducing Ig synthesis, we set up an in vitro help assay.
JHD or normal BALB/c mice were injected i.p. with KLH in CFA, and 7 to
9 days later the primed, CD4+ T cells were purified as
described above. TNP-conalbumin primed mice were used as a source of B
cells. The T and B cell populations were cultured together for 8 days
in vitro with varying concentrations of TNP-KLH. As shown in Figure 3 and Table I, normal KLH-primed BALB/c T cells
consistently provided help for TNP-specific Ab production, while primed
JHD T cells induced little or no detectable TNP-specific IgG secretion.
Because we used purified CD4+ T cells, and because T cells
and B cells were primed with different Ags, it is unlikely that the
TNP-specific IgG was produced by contaminating B cells in the T cell
(KLH-primed) population or that contaminating T cells in the B cell
population induced Ig synthesis. Despite the inability of primed JHD T
cells to provide help, the cultures with JHD T cells proliferated
normally and induced amounts of TNP-specific IgM equivalent to control
cultures with primed BALB/c T cells (data not shown). The failure of
Ag-primed JHD T cells to help was not due to suppression,
since mixtures of BALB/c and JHD T cells were very effective at
inducing TNP-specific Ab production (Fig. 4). Optimal Ig production was observed
when low numbers of BALB/c T cells were used (1.5 x
106), and Ig production declined with higher numbers of T
cells (3 x 106). As shown in Figure 4, when equal
numbers of BALB/c and JHD T cells totaling 3 x 106
were used as helper cells, the amount of TNP-specific IgG produced was
similar to that observed with 3 x 106 BALB/c T
cells.
|
|
|
As expected, IgG1 was the predominant isotype present in the
supernatants from help assays with normal Ag-primed T cells (data not
shown). Because isotype switching to IgG1 is mediated by IL-4 (19), we
hypothesized that the JHD T cells produced less IL-4 in response to B
cells than did T cells from normal mice. We examined JHD T cell
responses to B cell Ag presentation using mitomycin C-treated MD4 Ig
receptor transgenic B cells, which express surface Ig specific for the
Ag HEL (10). These B cells were used to present an HEL-OVA protein
conjugate to T cells primed to OVA in a unique system that allows
highly efficient Ag presentation by Ag-specific B cells (11). Using
this system, we found that the JHD T cells only secrete 30 ±
8.3% (p < 0.05, by Student’s paired
t test) as much IL-4 as normal BALB/c T cells (Fig. 5). Previously, using SpAC as APCs, we
found that IL-4 production by OVA-primed JHD T cells was similar to
that by OVA-primed T cells from normal mice (Fig. 2C), although the absolute amount of IL-4 induced
with SpAC was much lower than that induced with Ag-specific B cells as
APCs (11). Therefore, we directly compared the responses of JHD and
BALB/c T cells to Ag presented by SpAC or B cells. The OVA-primed JHD T
cells proliferated to a similar extent as OVA-primed normal T cells in
response to SpAC or B cells (Fig. 6A). However, while
IL-4 production by JHD T cells was equivalent to that of normal T cells
when SpAC were used as APC, the JHD T cells produced significantly less
IL-4 than did normal T cells when B cells presented Ag (Fig. 6B). We also assayed IFN- and IL-5 in these
cultures. We found that, like IL-4, IFN- was reduced in JHD cultures
with B cells as APC, but not in those with SpAC (Fig. 7A). Surprisingly, IL-5
was consistently increased in all cultures with JHD T cells (Fig. 7B).
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
compared
with primed T cells from normal mice and were unable to induce
Ag-specific IgG production from the Ag-presenting B cells. We undertook these experiments with JHD mice to resolve conflicting reports concerning the importance of B cells in T cell priming and the ability of T cells primed in the absence of B cells to provide B cell help. Older studies using anti-IgM-treated mice suggested that B cells are required for T cell priming (1, 2, 3), but more recent studies with B cell-deficient mice have given disparate results (6, 7, 8, 9). Likewise, there have been conflicting reports as to whether T cells primed in B cell-deficient mice can provide help for B cells (8, 9, 20).
Our studies addressed the issue of T cell priming in the absence of B
cells using clearly defined experimental systems with highly purified
populations of T cells and B cells. First, we used JHD mice, which have
a targeted deletion of the JH region and have been
found to be completely free of both B cells and serum Ab (5). In
contrast, previous in vivo experimental systems using mice treated from
birth with anti-IgM Ab were much less likely to be completely free
of B cells or Ig. More recently, researchers have used µMT mice,
which have a targeted deletion of the µ region, but are reported to
have low levels of 
-chain rearrangements (21). Second, our in vitro
studies are highly reliable because we used extremely pure populations
of Ag-primed T cells, devoid of functional APC. Contaminating B cells
in control populations of primed normal T cells can potentially be very
effective in presenting Ag and can falsely increase the proliferative
response of such T cells from normal mice. We, therefore, used a
three-step protocol to purify T cells, which produced T cell
populations that failed to proliferate in response to Ag in the absence
of added APCs. When fully purified Ag-primed CD4+ T cells
from normal mice were compared with those from JHD mice, no difference
in the proliferative or cytokine responses to Ag with SpAC were
observed (Fig. 2). We conclude that effective purification of the
control T cell population is a key difference between reports that T
cells in B cell-deficient mice can or cannot be primed.
Our observation that Ag-primed JHD T cells fail to induce IgG
production was unexpected, since the JHD T cells responded normally by
all other measures (Fig. 2), and we used mice with the BALB/c
background, which are predisposed toward Th2/humoral immune responses.
The data were reproduced in multiple independent experiments (Table I),
and in all instances, significantly reduced IgG production was noted
when Ag-primed T cells from JHD mice were used. The TNP-specific IgG
synthesis we observed in help assays using normal control T cells was
dependent upon cognate T cell-B cell interactions, and only occurred
when T cells, B cells, and specific Ag were all present. Additionally,
the capacity of Ag-primed T cells to induce Ig synthesis was determined
using a hapten carrier system that avoided the possibility that the B
cell population was contaminated by Th cells. Finally, it is unlikely
that the Ag-primed JHD T cells were cytotoxic for B cells, since JHD T
cells did not inhibit the ability of normal T cells to induce Ig
synthesis in mixing experiments (Fig. 4).
The failure of Ag-primed T cells from JHD mice to induce IgG synthesis
appears to be due to a failure of such T cells to induce isotype
switch, since the proliferation and induction of TNP-specific IgM
production occurred normally in these cultures. The two major signals
required for B cell isotype switch from IgM to IgG1 are IL-4R
engagement and CD40 cross-linking (19). These signals are provided by
Th cells, but may not be provided by primed T cells from JHD mice. As
shown in Figure 6, JHD T cells proliferated normally when stimulated
with Ag plus SpAC or Ag plus B cells, but these T cells secreted much
less IL-4 in response to Ag presented by B cells (Fig. 6). These
results suggest that a decrease in IL-4 secretion caused the failure of
JHD T cells to provide adequate help for B cells. Although the
reduction in IL-4 synthesis by JHD T cells is less dramatic than the
decrease in help for Ab production, a linear relationship between IL-4
and isotype switch to IgG1 may not exist. Furthermore, for the
induction of IgG1, high concentrations of IL-4 may be required only in
the immediate B cell microenvironment, a hypothesis that is supported
by our inability to detect IL-4 in the supernatants of our help assay
cultures (data not shown).
We have attempted to reconstitute help by adding IL-4 (5–2500 pg/ml) to help assays with either normal or JHD T cells. IgG production increased greatly in response to IL-4 in the cultures with normal T cells, but was only slightly increased in cultures containing JHD T cells. Addition of IL-4 to JHD cultures did not increase IgG production to the level seen in cultures with normal BALB/c cultures that did not have IL-4 added (data not shown). This suggests that reduced IL-4 production is only partially responsible for the inefficient induction of IgG synthesis by JHD T cells.
The second signal required by B cells for isotype switch is CD40 cross-linking, which coincidentally also provides a costimulatory signal to T cells via CD40L cross-linking, which enhances IL-4 synthesis (22). We compared up-regulation of CD40L expression in both normal and JHD T cells in response to anti-CD3 stimulation and found that CD40L is up-regulated to the same extent (data not shown). However, we were unable to determine whether primed JHD T cells up-regulate CD40L in response to Ag presented by B cells because Ag-specific T cells make up a very small percentage of the cells in a primed LN and cannot be readily identified by FACS. In a different approach, we added anti-CD40 mAb 1C10 to cultures of B cells and JHD T cells as a substitute for CD40L stimulation, since this mAb has been shown to stimulate B cell proliferation (23). We found that a range of concentrations (0.1–10 µg/ml) of the mAb blocked TNP-specific IgG production in help assays with normal T cells and did not increase IgG production in help assays with JHD T cells (data not shown). It is possible that this Ab did not provide an effective signal to the B cell or that it interfered with help by blocking T-B interactions. Alternatively, it is possible that CD40 stimulation of B cells with IL-4 must be provided more directly to Ag-specific B cells, presumably by T cells, for TNP-specific IgG production to be observed. Therefore, we cannot as yet conclude whether CD40L expression is normal in Ag-primed JHD T cells responding to B cell APCs or whether primed JHD T cells are defective in signaling B cells through CD40.
Our demonstration that T cells from JHD mice are unable to provide effective help for B cells is in agreement with two other reports. Liu et al. reported that JHD T cells could not induce Ig synthesis; however, they did not use highly purified CD4+ T cells and reported that primed T cells from JHD mice did not proliferate after secondary stimulation with Ag (8). Epstein et al. cited unpublished work by Roes and Rajewsky suggesting that T cells from µMT mice cannot be primed to help (9). In contrast, Oxenius et al. reported that neither CD40 expression nor the presence of B cells is necessary for the development of Th cells (20). Using a T cell transfer system, Oxenius et al. showed that T cells from either µMT or CD40 knockout mice infected with LCMV could help to mediate isotype switching when transferred into normal naive mice. These conflicting results may reflect a difference in the predominant cytokines and isotypes present during LCMV infection (Th1) vs priming with Ag (Th0). It is also possible that viral infection activates APCs in such a way as to give different signals to responding T cells than adjuvant activation does.
The defects we have observed in the interaction of primed JHD T cells with B cells in vitro may be due to the absence of a signal normally provided by B cells during in vivo priming. Given van Essen et al.’s finding that T cells primed in CD40-deficient mice are unable to provide B cell help (24) and our finding that CD40L signaling can stimulate T cell IL-4 synthesis (22), it is likely that the interaction between CD40 on the B cell and CD40L on the T cell provides a critical signal in the development of Th cells. Signaling via CD40, CD40L, or both could be important in this process. Abs to human CD40L can induce T cell proliferation (25) and IL-4 secretion (22), and blocking the CD40L signal can inhibit T cell IL-4 production (11, 26). Although other APCs express CD40, B cells express higher levels (11, 23, 27), which may be necessary for these responses.
The signal that B cells receive via CD40 during T-B interaction could also be important to Th cell development. Signaling via CD40 on B cells has a number of effects, including stimulation of isotype switch and proliferation (28), and up-regulation of costimulatory molecules such as B7-1 and B7-2 (29, 30). Liu’s group also reported that signaling via CD40 on B cells up-regulates CD44H, which acts as an early costimulatory signal for T cell proliferation (31, 32). Expression of this isoform of CD44 may be limited to B cells, which could explain why JHD T cells respond normally to other APCs but not to B cells. Future experiments are focused on determining which costimulatory molecules may account for this unique ability of B cells to provide a stimulus to T cells that is not replicated by other APC populations and that is necessary for future productive T-B interactions.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. D. T. Umetsu, Division of Immunology and Transplantation Biology, Department of Pediatrics, Room H307, Stanford University, Stanford, CA 94305–5119.
3 Abbreviations used in this paper: LN, lymph node; SpAC, splenic adherent cells; HEL, hen egg lysozyme; HEL-OVA, protein conjugate between hen egg lysozyme and OVA; KLH, keyhole limpet hemocyanin; TNP, trinitrophenyl; Tg, transgenic.
Received for publication July 11, 1997. Accepted for publication October 29, 1997.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  C. Ronet, H. Voigt, H. Himmelrich, M.-A. Doucey, Y. Hauyon-La Torre, M. Revaz-Breton, F. Tacchini-Cottier, C. Bron, J. Louis, and P. Launois Leishmania major-Specific B Cells Are Necessary for Th2 Cell Development and Susceptibility to L. major LV39 in BALB/c Mice J. Immunol., April 1, 2008; 180(7): 4825 - 4835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Maglione, J. Xu, and J. Chan B Cells Moderate Inflammatory Progression and Enhance Bacterial Containment upon Pulmonary Challenge with Mycobacterium tuberculosis J. Immunol., June 1, 2007; 178(11): 7222 - 7234. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M Strutt, J. Uzonna, K. K McKinstry, and P. A Bretscher Activation of thymic T cells by MHC alloantigen requires syngeneic, activated CD4+ T cells and B cells as APC Int. Immunol., May 1, 2006; 18(5): 719 - 728. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Crawford, M. MacLeod, T. Schumacher, L. Corlett, and D. Gray Primary T Cell Expansion and Differentiation In Vivo Requires Antigen Presentation by B Cells J. Immunol., March 15, 2006; 176(6): 3498 - 3506. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Mozdzanowska, M. Furchner, D. Zharikova, J. Feng, and W. Gerhard Roles of CD4+ T-Cell-Independent and -Dependent Antibody Responses in the Control of Influenza Virus Infection: Evidence for Noncognate CD4+ T-Cell Activities That Enhance the Therapeutic Activity of Antiviral Antibodies J. Virol., May 15, 2005; 79(10): 5943 - 5951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Byersdorfer, R. J. DiPaolo, S. J. Petzold, and E. R. Unanue Following Immunization Antigen Becomes Concentrated in a Limited Number of APCs Including B Cells J. Immunol., December 1, 2004; 173(11): 6627 - 6634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Attanavanich and J. F. Kearney Marginal Zone, but Not Follicular B Cells, Are Potent Activators of Naive CD4 T Cells J. Immunol., January 15, 2004; 172(2): 803 - 811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Liu, Q. Liu, J. Pesce, J. Whitmire, M. J. Ekkens, A. Foster, J. VanNoy, A. H. Sharpe, J. F. Urban Jr., and W. C. Gause Nippostrongylus brasiliensis Can Induce B7-Independent Antigen-Specific Development of IL-4-Producing T Cells from Naive CD4 T Cells In Vivo J. Immunol., December 15, 2002; 169(12): 6959 - 6968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. F. Cunningham, P. G. Fallon, M. Khan, S. Vacheron, H. Acha-Orbea, I. C. M. MacLennan, A. N. McKenzie, and K.-M. Toellner Th2 Activities Induced During Virgin T Cell Priming in the Absence of IL-4, IL-13, and B Cells J. Immunol., September 15, 2002; 169(6): 2900 - 2906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Tsitoura, V. P. Yeung, R. H. DeKruyff, and D. T. Umetsu Critical role of B cells in the development of T cell tolerance to aeroallergens Int. Immunol., June 1, 2002; 14(6): 659 - 667. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Paroli, D. Accapezzato, V. Francavilla, A. Insalaco, A. Plebani, F. Balsano, and V. Barnaba Long-lasting memory-resting and memory-effector CD4+ T cells in human X-linked agammaglobulinemia Blood, March 15, 2002; 99(6): 2131 - 2137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Topilski, A. Harmelin, R. A. Flavell, Y. Levo, and I. Shachar Preferential Th1 Immune Response in Invariant Chain-Deficient Mice J. Immunol., February 15, 2002; 168(4): 1610 - 1617. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ramakrishna, S. A. Stohlman, R. D. Atkinson, M. J. Shlomchik, and C. C. Bergmann Mechanisms of Central Nervous System Viral Persistence: the Critical Role of Antibody and B Cells J. Immunol., February 1, 2002; 168(3): 1204 - 1211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. McNeal, J. L. VanCott, A. H. C. Choi, M. Basu, J. A. Flint, S. C. Stone, J. D. Clements, and R. L. Ward CD4 T Cells Are the Only Lymphocytes Needed To Protect Mice against Rotavirus Shedding after Intranasal Immunization with a Chimeric VP6 Protein and the Adjuvant LT(R192G) J. Virol., January 15, 2002; 76(2): 560 - 568. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Rivera, C.-C. Chen, N. Ron, J. P. Dougherty, and Y. Ron Role of B cells as antigen-presenting cells in vivo revisited: antigen-specific B cells are essential for T cell expansion in lymph nodes and for systemic T cell responses to low antigen concentrations Int. Immunol., December 1, 2001; 13(12): 1583 - 1593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Sugie and J. Huang GIF Inhibits Th Effector Generation by Acting on Antigen-Presenting B Cells J. Immunol., April 1, 2001; 166(7): 4473 - 4480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Braley-Mullen and S. Yu Early Requirement for B Cells for Development of Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice J. Immunol., December 15, 2000; 165(12): 7262 - 7269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-J. Linton, J. Harbertson, and L. M. Bradley A Critical Role for B Cells in the Development of Memory CD4 Cells J. Immunol., November 15, 2000; 165(10): 5558 - 5565. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Moulin, F. Andris, K. Thielemans, C. Maliszewski, J. Urbain, and M. Moser B Lymphocytes Regulate Dendritic Cell (Dc) Function in Vivo: Increased Interleukin 12 Production by DCs from B Cell-Deficient Mice Results in T Helper Cell Type 1 Deviation J. Exp. Med., August 21, 2000; 192(4): 475 - 482. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Hansen, S.-L. C. Jin, D. T. Umetsu, and M. Conti Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D PNAS, June 6, 2000; 97(12): 6751 - 6756. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Baumgarth, G. C. Jager, O. C. Herman, L. A. Herzenberg, and L. A. Herzenberg CD4+ T cells derived from B cell-deficient mice inhibit the establishment of peripheral B cell pools PNAS, April 25, 2000; 97(9): 4766 - 4771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Evans, M. W. Munks, J. M. Purkerson, and D. C. Parker Resting B Lymphocytes as APC for Naive T Lymphocytes: Dependence on CD40 Ligand/CD40 J. Immunol., January 15, 2000; 164(2): 688 - 697. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Hansen, V. P. Yeung, G. Berry, D. T. Umetsu, and R. H. DeKruyff Vaccination with Heat-Killed Listeria as Adjuvant Reverses Established Allergen-Induced Airway Hyperreactivity and Inflammation: Role of CD8+ T Cells and IL-18 J. Immunol., January 1, 2000; 164(1): 223 - 230. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Elkins, C. M. Bosio, and T. R. Rhinehart-Jones Importance of B cells, but Not Specific Antibodies, in Primary and Secondary Protective Immunity to the Intracellular Bacterium Francisella tularensis Live Vaccine Strain Infect. Immun., November 1, 1999; 67(11): 6002 - 6007. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Coffin, S. L. Clark, N. A. Bos, J. O. Brubaker, and P. A. Offit Migration of Antigen-Presenting B Cells from Peripheral to Mucosal Lymphoid Tissues May Induce Intestinal Antigen-Specific IgA Following Parenteral Immunization J. Immunol., September 15, 1999; 163(6): 3064 - 3070. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Vora, K. M. Tumas-Brundage, V. M. Lentz, A. Cranston, R. Fishel, and T. Manser Severe Attenuation of the B Cell Immune Response in Msh2-deficient Mice J. Exp. Med., February 1, 1999; 189(3): 471 - 482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Bretscher A two-step, two-signal model for the primary activation of precursor helper T cells PNAS, January 5, 1999; 96(1): 185 - 190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Brown and S. L. Reiner Polarized Helper-T-Cell Responses against Leishmania major in the Absence of B Cells Infect. Immun., January 1, 1999; 67(1): 266 - 270. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
