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* Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
Pulmonary and Critical Care Division, Department of Medicine, University of California, San Francisco, CA 94143;
Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and
Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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+ T cells and B7-dependent costimulation,
although only PspA-specific memory was generated. In this report, we
show that the T cell help underlying these two Ag-specific Ig responses
is distinct. Using H-Y-specific T cell transgenic mice made
"nonleaky" by crossing with mice genetically deficient for TCR-,
we demonstrate that the T cell help for the anti-PC, in contrast to
the anti-PspA, response is TCR-nonspecific and occurs normally in
the absence of germinal center formation, although it is still
dependent on B7-dependent costimulation. Consistent with these data, we
demonstrate, using cathepsin S-/- mice, that although the
anti-PC response is largely dependent on CD4+ T cells,
there is a reduced (or lack of) dependence, relative to the
anti-PspA response, on the generation of new peptide-MHC class II
complexes. In this regard, the T cell help for an optimal anti-PC
response is delivered more rapidly than that required for an optimal
anti-PspA response. Collectively, these data demonstrate a novel
accelerated TCR-nonspecific B7-dependent form of T cell help for
augmenting a polysaccharide-specific Ig response to an intact bacterium
without the generation of memory. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In vitro studies suggest a potential role for non-T cells, such as dendritic cells (DC), macrophages, and/or NK cells, in providing B cell help for an anti-polysaccharide response through their release of cytokines and/or their membrane expression of B cell activating ligands (6, 7, 8, 9, 10, 11). Some in vivo studies demonstrate that NK cells can regulate Ig isotype selection (12, 13), and that APCs, through their release of B lymphocyte stimulator, may stimulate B cell maturation in response to T cell-independent Ags (14, 15). Although polysaccharides fail to associate with MHC molecules (3) and hence cannot directly recruit cognate T cell help, their coexpression with proteins by an intact pathogen could in theory mediate cognate CD4+ T cell help for polysaccharide-specific B cells, similar to the mechanism underlying the effectiveness of soluble protein-polysaccharide conjugate vaccines (16, 17). In this regard, it was recently demonstrated that blocking CD40-CD40-ligand interactions during an in vivo response to intact Streptococcus pneumoniae, using an anti-CD40-ligand mAb, inhibited induction of Ig specific for capsular, but not cell wall, polysaccharide. This suggested a possible role for cognate T cell help for the anti-capsular polysaccharide response (18). In contrast, anti-CD40-ligand mAb has no effect on the in vivo trinitrophenyl (TNP)-specific Ig response to the soluble T cell-independent Ag, trinitrophenyl-Ficoll (19). A number of additional mechanisms have been proposed whereby T cells could potentially regulate anti-polysaccharide Ig responses, although there is no published data that these are operative during an in vivo response to an intact pathogen (1).
Early in vivo studies demonstrated that T cells could regulate anti-polysaccharide responses in either a positive or negative manner, or influence B cell repertoire or Ig isotype selection (1, 20, 21, 22, 23, 24, 25). In addition, it has been shown that an in vivo anti-polysaccharide response to an intact bacteria is diminished in athymic nude mice, which have a congenital deficiency in T cells (26, 27). Although collectively these studies demonstrated diverse roles for T cells in regulating anti-polysaccharide responses, the majority of these used purified soluble polysaccharides, with or without haptenation, that may not reflect physiologic polysaccharide-specific Ig responses to a biochemically diverse intact pathogen. Further, these studies did not elucidate the underlying mechanism(s) for these T cell effects. In particular, the central question of whether T cells regulate in vivo anti-polysaccharide Ig responses to intact pathogens in a cognate or noncognate manner has not yet been answered.
In a previous study of the in vivo humoral response to intact S.
pneumoniae (strain R36A), we demonstrated a requirement for
TCR-+ T cells and B7-dependent
costimulation for stimulating IgG responses specific for both the cell
wall protein, pneumococcal surface protein A (PspA), and the
phosphorylcholine (PC) determinant of the cell wall C-polysaccharide
(teichoic acid) (28, 29). Of interest, primary
immunization with R36A generated little, if any, PC-specific IgG
memory, whereas the anti-PspA response in R36A-primed mice was
boosted 10- to 20-fold in response to secondary immunization. In
addition, the IgG anti-PC response occurred with significantly more
rapid kinetics than that observed for induction of PspA-specific IgG.
Collectively, these data suggested the possibility that T cells might
play distinct roles in these two responses. In the current study, we
confirm this hypothesis and provide strong evidence that unlike the T
cell help for the anti-PspA response which is cognate, the T cell
help for the anti-PC response is TCR-nonspecific.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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H-Y -/- mice were created through
introduction of the H-Y (male Ag) TCR transgene into
TCR--/- mice as previously described
(30). Cathepsin S-/- mice were
generated as previously described through deletion of the cathepsin S
gene exon 5 which contains the active site cysteine of murine cathepsin
S and were bred greater than nine generations into the C57BL/6
background (31). B6,129 F2
mice (The Jackson Laboratory, Bar Harbor, ME) were used as
controls for H-Y -/- mice, and C57BL/6 mice
(The Jackson Laboratory) were used as controls for cathepsin
S-/- mice. Athymic nude and control BALB/c mice
were purchased from NCI (Frederick, MD). All mice were used between 6
and 10 wk of age.
Reagents
PC-BSA and PC-keyhole limpet hemocyanin (KLH), kind gifts
of Dr. A. Lees (Biosynexus, Rockville, MD), were synthesized as
described previously (28). rPspA, a kind gift of Dr. L.
Grinberg (Biosynexus) was expressed in Saccharomyces
cerevisiae BJ3505 as a His6-tagged fusion
protein, and purified by Ni-NTA affinity chromatography
(28). The expressed protein includes aa 4–299 of the
mature protein. Murine CTLA4Ig and a control fusion protein, L6 was
prepared as previously described (32). Rat IgG2b
anti-mouse CD4 mAb (GK1.5) and rat IgG2b anti-mouse CD8 mAb
(2.43) were purified from ascites by ammonium sulfate precipitation and
passage over a protein G column. Purified rat IgG was purchased from
Accurate Chemical and Scientific (Westbury, NY). FITC-hamster IgG1
anti-murine CD3
mAb (clone 145-2C11), PE-rat IgG2b
anti-murine CD4 mAb (clone GK1.5), and PE-rat IgG2a
anti-murine CD8 mAb (clone 5.3-6.7) (BD PharMingen, San Diego, CA)
were used for flow cytometry.
Preparation of, and immunization with, R36A
A nonencapsulated variant (strain R36A) of virulent S. pneumoniae capsular type 2 (strain D39) (33) was grown in Todd-Hewitt broth to mid-log phase and stored at -70°C. For immunization, frozen bacteria were thawed and subcultured on blood agar plates. One to two characteristic colonies were selected and suspended in 200 ml of Todd-Hewitt broth, placed in a shaker water bath at 37°C for 4–6 h until an OD (absorbance at 650 nm) of 0.6 was achieved as measured by a spectrophotometer (Spectronic 100; Bausch & Lomb, Rochester, NY). The 200-ml prep of R36A was then heat-killed by incubation in a 60°C water bath for 10 h (1 h/20 ml). Sterility was confirmed by culture. This bacterial stock, containing 1 x 109 CFU/ml, was aliquoted and frozen at -70°C until used for immunization. Mice were immunized i.p. with 2 x 108 CFU R36A in 250 µl of PBS. Serum samples for measurement of anti-PC and anti-PspA Ab titers were prepared from blood obtained through the tail vein.
Measurement of serum Ag-specific Ig isotype titers
Immulon 2 plates were coated with PC-KLH or PC-BSA (5 µg/ml) and Immulon 4 plates were coated with PspA (5 µg/ml) in 1x PBS for 1 h at 37°C or overnight at 4°C. Plates were then blocked with blocking buffer (1x PBS + 0.5% BSA) at 37°C for 30 min or 4°C overnight. Three-fold dilutions of serum samples in blocking buffer were then added starting at a 1/50 serum dilution. After a 1 h incubation at 37°C, plates were washed thee times with PBT (1x PBS + 0.1% Tween 20). Alkaline phosphatase-conjugated polyclonal goat anti-mouse IgM, IgG3, IgG1, IgG2b, and IgG2a Abs (200 ng/ml final concentration in blocking buffer) were then added and plates were incubated for 37°C for 1 h. Plates were washed five times with PBT. Substrate (4-methylumbelliferyl phosphate) was then added (50 µg/ml, 50 µl/well) and fluorescence was read on MicroFLUOR ELISA reader (Dynatech Laboratories, Chantilly, VA).
Magnetic cell sorting
Magnetic cell sorting was performed according to manufacturer’s instructions (Miltenyi Biotec, Auburn, CA). Briefly, spleens were removed aseptically and spleen cells were suspended in cold HBSS + 3% FCS (BioWhittaker, Walkersville, MD). RBCs were lysed with ACK lysing buffer (BioWhittaker). Cells were then suspended for 20 min in sorting buffer (Dulbecco’s PBS + 0.5% BSA + 2 mM EDTA) at 1 x 108 cells/ml in the presence of 100 µl/ml of either mouse CD8a (Ly-2) or mouse CD4 (L3T4) MicroBeads (Miltenyi Biotec). Cells were then washed in 20 volumes of sorting buffer to remove unattached MicroBeads and resuspended into sorting buffer (1 x 109 cells/3 ml). Cells were then loaded onto an LS MACS separation column (Miltenyi Biotec) on a MidiMACS magnetic separator. Cells retained in the column were washed, the column was removed from the separator, and then flushed with sorting buffer to recover retained cells. Cell purities were determined by flow cytometry and typically demonstrated purities of 95–99% for both CD4+ and CD8+ T cells.
Adoptive transfer
Two or 6 x 106 BALB/c-derived CD4+ or CD8+ T cells obtained by magnetic cell sorting were suspended in 0.4 ml PBS in the presence of 1 mg of anti-CD8 or anti-CD4 mAb, respectively, and injected i.v. into athymic nude mice. Mice were then challenged 16 h later with R36A. Serum was obtained on day 7 for anti-PC titers and on day 14 for anti-PspA titers.
Quantitation of germinal centers by immunohistochemistry
The staining procedure for detection of germinal centers has been described previously. Briefly, spleens were removed from unimmunized mice and from mice 14 days after i.p. immunization with R36A. Sections (8 µm) were cut, fixed in acetone for 10 min, and stored at -70°C. Germinal center B cells were stained with 15 µg/ml of FITC-peanut agglutinin (ICN Pharmaceuticals, Costa Mesa, CA) for 1 h at room temperature. Slides were washed with PBS, allowed to dry, then covered with Fluoromount-G (Southern Biotechnology Associates, Birmingham, AL) for analysis by fluorescence microscopy using a Zeiss Axiophot fluorescence microscope (Oberkochen, Germany).
Statistics
Data is expressed as the arithmetic mean of Ig titers of individual serum samples ± SEM. Differences between treatment groups were considered significant at p < 0.05 using the Student t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We previously demonstrated that the IgG anti-PspA and IgG
anti-PC response to R36A was dependent upon
TCR-+ T cells and B7-dependent
costimulation (28). A subsequent study indicated that a
shorter period of costimulation was required for an optimal
anti-PC, relative to an optimal primary anti-PspA response
(29). In this regard, we wished to determine whether this
was associated with a requirement for a shorter period of T cell help
to mediate the anti-PC response. To accomplish this, we acutely
depleted T cells on different days (-1, 0, 1, 3, 5, and 7) after R36A
immunization using a combination of anti-CD4 + anti-CD8 mAbs
and measured serum titers of IgG anti-PC and IgG anti-PspA on
days 7 and 14, respectively, which are the times at which optimal Ig
titers are observed (28, 29) (Fig. 1
). A similar dose of total rat IgG was
injected on day -1 as a control. Injection of T cell-depleting mAbs 1
day after R36A immunization resulted in a significantly higher IgG
anti-PC response to R36A relative to that obtained when mAbs were
injected on days -1 or 0, whereas in distinct contrast, there was
still a complete inhibition in induction of PspA-specific IgG titers.
Injection of mAbs 3 days after R36A immunization had no significant
effect on the IgG anti-PC response but was still associated with a
significant, though partial, inhibition of the IgG anti-PspA
response. Injection of mAb on day 5 had no effect on either response.
These data indicate that a shorter period of T cell help is sufficient
for mediating an optimal IgG anti-PC vs anti-PspA response and
is consistent with our previous observation of a comparably reduced
time requirement for B7-dependent costimulation (29).
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In a previous study we observed that injection of anti-CD4 mAb
alone was sufficient for complete inhibition of the IgG anti-PspA
response to R36A (28). In contrast, maximal inhibition of
the IgG anti-PC response required injection of both anti-CD4 +
anti-CD8 mAbs. Although in vitro studies have demonstrated that
CD8+ T cells can stimulate Ig induction by B
cells, they were less effective than CD4+ T
cells, perhaps in part due to lower CD40 ligand expression
(34). To better define the relative contributions of
CD4+ and CD8+ T cells for
mediating help for the IgG anti-PC response to R36A, we purified
splenic CD4+ and CD8+ T
cells from naive mice and adoptively transferred them (2 x
106 and 6 x 106 T
cells per mouse) into T cell-deficient, athymic nude mice, 1 day before
R36A immunization. Purified CD4+ and
CD8+ T cells had 
1–2%
cross-contaminating T cells as determined by flow cytometry (data not
shown). In this regard, purified CD4+ and
CD8+ T cells were mixed with 1 mg/mouse of
anti-CD8 mAb or anti-CD4 mAb, respectively, to deplete any
residual contaminating T cells upon in vivo transfer. Athymic nude
mice, injected with R36A alone, demonstrated no detectable IgG
anti-PspA, and a strongly reduced IgG anti-PC, response (Fig. 2). Transfer of
CD4+, but not CD8+, T cells
to athymic nude mice led to a significant induction of IgG
PspA-specific titers, comparable to what is typically observed using
control euthymic mice. Likewise, transfer of CD4+
T cells led to a substantial up-regulation in the IgG, but not IgM,
anti-PC response. The IgM anti-PC response is typically not
reduced or only modestly reduced in mice lacking T cells relative to
control mice (28). In contrast to the anti-PspA
response, transfer of CD8+ T cells induced a
modest increase in IgG anti-PC titers that variably reached
statistical significance, but this effect was strikingly lower on a per
cell basis than that observed for the IgG anti-PC response after
transfer of CD4+ T cells. These data indicate
that although CD8+ T cells may play some role in
stimulating in vivo IgG anti-PC responses,
CD4+ T cells are significantly more efficient
helpers.
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Although polysaccharides do not associate with MHC molecules
(3), thus typically precluding TCR-specific (cognate) T
cell recognition of such Ags, the coexpression of polysaccharides with
proteins by an intact pathogen could allow for cognate T cell help for
polysaccharide-specific B cells, similar to the mechanism underlying
the effectiveness of soluble protein-polysaccharide conjugate vaccines
(16, 17). Additionally, direct TCR recognition of
polysaccharide Ags, independent of MHC molecules, has been described
(35, 36). To determine whether specific TCR recognition
was required for T cell help for the IgG anti-PC response, we used
a mouse that expressed a single TCR specificity for an Ag not present
within R36A. Because all TCR transgenic mice exhibit variable degrees
of endogenous TCR gene rearrangements leading to a T cell repertoire
with multiple specificities, we used a TCR transgenic mouse (specific
for the male, H-Y Ag in association with MHC class I) that had
previously been crossed with mice genetically deficient in TCR-
(designated H-Y -/-) (30).
These mice expressed no endogenous TCR, possessed relatively normal
numbers of CD4+ and CD8+ T
cells, and had normal numbers of B cells. CD8+ T
cells in H-Y -/- mice expressed specificity
for H-Y, whereas CD4+ T cells were
idiotype-negative, but did express TCR-, perhaps in association with
another undetermined protein. Importantly, although both the
idiotype-positive and -negative T cells from H-Y
-/- mice had functional TCR, as indicated by
responsiveness to Con A, they failed to respond to a conventional
protein Ag in adjuvant. This observation is consistent with other
reports using nontransgenic TCR--/- mice
which also demonstrate complete abrogation of Ig responses to
conventional protein Ags (37, 38). H-Y
-/- and nontransgenic wild-type mice were
thus immunized with optimal and suboptimal doses of R36A, and serum
titers of IgG anti-PC and IgG anti-PspA isotypes were measured
on the indicated days. As shown in Fig. 3, H-Y -/-
mice elicited no detectable primary anti-PspA response of any IgG
isotype after immunization with either optimal or suboptimal doses of
R36A. Secondary challenge with R36A also failed to elicit a detectable
anti-PspA response (data not shown). In contrast, R36A-induced
titers of IgG anti-PC of all isotypes were essentially equivalent
in H-Y -/- and control mice using either
optimal or suboptimal doses of R36A (Fig. 3). Whereas, R36A
immunization of control mice induced a significant germinal center
reaction, no detectable germinal centers were observed in either
unimmunized or immunized H-Y -/- mice (Fig. 4) consistent with the lack of response
of H-Y -/- mice to immunization with
conventional protein Ag (30) and our previous
demonstration of a lack of memory generation for the IgG anti-PC
response (28, 29). The elicitation of Ig-secreting cells
in wild-type mice, outside of the germinal center environment
following immunization with either protein or polysaccharide Ag, is
well described (39, 40).
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-/- mice
was in fact T cell-dependent, as previously observed in control mice
(28), and whether these T cells also required B7-dependent
costimulation to mediate helper activity. Thus, H-Y
-/- and control mice were injected with a
combination of anti-CD4 + anti-CD8 mAbs or control rat IgG, 1
day before R36A immunization. As illustrated in Fig. 5A, depletion of T cells
resulted in a complete abrogation of the anti-PspA response in
wild-type mice. Although T cell depletion had no significant effect on
the IgM anti-PC response either in H-Y
-/- or wild-type mice, PC-specific IgG
isotypes were significantly and comparably reduced in T cell-depleted
H-Y -/- and wild-type mice, relative to mice
treated with control rat IgG. Likewise, H-Y
-/- mice treated with CTLA4Ig showed a
significant reduction in PC-specific IgG isotypes, although no change
in the IgM anti-PC response (Fig. 5B), consistent with
previous data using wild-type mice (28). In an additional
experiment, H-Y -/- mice were injected
separately with either anti-CD4, anti-CD8, or control mAb, and
the anti-PC response was measured 7 days after R36A immunization
(Fig. 6). A substantial reduction (3- to
5-fold) in the IgG, but not IgM, anti-PC response, relative to mice
treated with control mAb, was observed in anti-CD4-injected H-Y
-/- mice, with only a modest reduction in
IgG anti-PC titers observed in mice treated with anti-CD8.
Collectively these experiments strongly suggest that, unlike the
anti-PspA response, the CD4+ T cell help for
the anti-PC response is TCR-nonspecific, but B7-dependent.
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Cognate interactions between APCs and T cells require APC
processing of protein Ags into peptides, loading of peptides onto MHC
molecules, and subsequent transport of peptide-MHC complexes to the APC
surface for presentation to T cells. APCs that lack the protease
cathepsin S are impaired in their ability to process the MHC class
II-associated invariant chain beyond a 10-kDa fragment, resulting in a
delay in peptide loading (41). Cathepsin
S-/- mice were previously shown to contain
normal numbers of B and T cells, but were significantly defective in
specific IgG responses to protein Ag in adjuvant (31).
Using cathepsin S-/- mice, we wished to test
the hypothesis that if the T cell help for the IgG anti-PC response
was TCR-nonspecific, it would not necessitate the acute processing of
bacterial protein for MHC-dependent presentation. As anticipated,
cathepsin S-/- mice showed a strong reduction
in both the primary and secondary IgG anti-PspA response to R36A
relative to wild-type mice (Fig. 7). In
contrast, the lack of cathepsin S had no significant effect on the IgG
anti-PC response consistent with the TCR-nonspecific nature of the
T cell help for induction of PC-specific IgG.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The parameters that mediate the TCR-nonspecific help for the IgG anti-PC response are currently under investigation. The requirement for B7-dependent costimulation suggests that these T cells express CD28 and physically interact with B cells, macrophages, and/or DCs expressing B7. In this regard, S. pneumoniae-pulsed DCs derived from mice doubly deficient in B7-1 and B7-2, while failing to induce an in vivo IgG anti-PspA response, stimulate a normal IgG anti-PC response (42). Nevertheless, this IgG anti-PC response is still blocked by injection of CTLA4Ig, suggesting that either B7-expressing macrophages and/or B cells can stimulate TCR-nonspecific T cells for augmentation of the IgG anti-PC response.
Optimal B7-dependent costimulation typically requires up-regulation of B7 on the APC. In response to S. pneumoniae, this will likely occur through Toll-like receptor-mediated signaling via bacterial DNA, peptidoglycan, and/or lipoteichoic acid (43). B7 up-regulation will occur in concert with APC release of multiple cytokines that could further costimulate T cells. The subthreshold TCR-mediated signaling that T cells receive through continual recognition of self peptide-MHC complexes (44, 45), in concert with B7-dependent and cytokine-mediated costimulation, may trigger sufficient T cell effector function for stimulation of the IgG anti-PC response. A recent in vitro study demonstrates that even certain combinations of cytokines alone can induce naive T cell proliferation, in the absence of TCR signaling (46).
It is likely that PC-specific B cells are strongly activated through multivalent mIg cross-linking by the repetitive PC moieties on the bacterial cell wall C-polysaccharide. This type of signaling would be expected to induce B cell proliferation alone, but in the presence of appropriate help, would costimulate Ig secretion and class switching (5, 6). TCR-nonspecific T cells, once activated, could provide this help either directly or indirectly. Thus, release of cytokines by these activated T cells either in contact with, or in close proximity to, mIg-activated PC-specific B cells could augment the IgG anti-PC response. Additionally, induction of TNF/TNFR family members on the surface of activated T cells, in contact with PC-specific B cells, could further costimulate B cell activation. Activated T cells could also stimulate APCs and other immune cells to release cytokines that might further amplify the B cell Ig response to bacterial challenge.
The rapid kinetics of the anti-PC, and other anti-polysaccharide Ig responses to extracellular bacteria may represent a distinct pathway of humoral immunity that contributes to early host protection against a rapidly dividing pathogen. The rapidity of this response may reflect the usage of distinct B cell subpopulations, such as B1 and marginal zone B cells (47, 48, 49), B cell tissue localization at sites of Ag entry, the potent mIg signaling in B cells mediated by polysaccharides expressing regularly spaced repeating identical antigenic epitopes (4), B cell helper activity of innate immune cells such as macrophages, DCs, and NK cells (6, 7, 8, 9, 10, 11, 12, 13, 14, 15), and as described in this study, the rapid recruitment of CD4+ Th cells. The accelerated kinetics of this T cell help may in part result from the TCR-nonspecific nature of the activational event, which would not necessitate the additional time required for Ag processing and presentation. Despite the TCR-nonspecific nature of this help, a level of specificity could be conferred by a requirement to strongly activate the polysaccharide-specific B cells through multivalent mIg cross-linking, which would then make B cells responsive to the action of cytokines and other forms of help (6).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Clifford M. Snapper, Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814. E-mail address: csnapper{at}usuhs.mil
3 Abbreviations used in this paper: mIg, membrane Ig; PspA, pneumococcal surface protein A; PC, phosphorylcholine; KLH, keyhole limpet hemocyanin; DC, dendritic cell.
Received for publication January 8, 2002. Accepted for publication March 28, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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3) dextran. I. Demonstration of an unexpected IgG response of athymic and germ-free-raised euthymic BALB/c mice. Eur. J. Immunol. 12:120.[Medline]
chain-deficient class I MHC-restricted TCR transgenic mice: role in a superantigen-mediated disease process. Int. Immunol. 11:1581./" T cells. J. Exp. Med. 183:2271.This article has been cited by other articles:
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  S. Vasilevsky, J. Colino, R. Puliaev, D. H. Canaday, and C. M. Snapper Macrophages Pulsed with Streptococcus pneumoniae Elicit a T Cell-Dependent Antibody Response upon Transfer into Naive Mice J. Immunol., August 1, 2008; 181(3): 1787 - 1797. [Abstract] [Full Text] [PDF]
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G. Chattopadhyay, A. Q. Khan, G. Sen, J. Colino, W. duBois, A. Rubtsov, R. M. Torres, M. Potter, and C. M. Snapper Transgenic Expression of Bcl-xL or Bcl-2 by Murine B Cells Enhances the In Vivo Antipolysaccharide, but Not Antiprotein, Response to Intact Streptococcus pneumoniae J. Immunol., December 1, 2007; 179(11): 7523 - 7534. [Abstract] [Full Text] [PDF]
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Q. Chen, G. Sen, and C. M. Snapper Endogenous IL-1R1 Signaling Is Critical for Cognate CD4+ T Cell Help for Induction of In Vivo Type 1 and Type 2 Antipolysaccharide and Antiprotein Ig Isotype Responses to Intact Streptococcus pneumoniae, but Not to a Soluble Pneumococcal Conjugate Vaccine J. Immunol., November 1, 2006; 177(9): 6044 - 6051. [Abstract] [Full Text] [PDF]
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 K. D. Salazar, P. de la Rosa, J. B. Barnett, and R. Schafer The Polysaccharide Antibody Response after Streptococcus pneumoniae Vaccination Is Differentially Enhanced or Suppressed by 3,4-Dichloropropionanilide and 2,4-Dichlorophenoxyacetic Acid Toxicol. Sci., September 1, 2005; 87(1): 123 - 133. [Abstract] [Full Text] [PDF]
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 K. S. Lee, G. Sen, and C. M. Snapper Endogenous CD4+ CD25+ Regulatory T Cells Play No Apparent Role in the Acute Humoral Response to Intact Streptococcus pneumoniae Infect. Immun., July 1, 2005; 73(7): 4427 - 4431. [Abstract] [Full Text] [PDF]
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K. G. McDonald, J. S. McDonough, and R. D. Newberry Adaptive Immune Responses Are Dispensable for Isolated Lymphoid Follicle Formation: Antigen-Naive, Lymphotoxin-Sufficient B Lymphocytes Drive the Formation of Mature Isolated Lymphoid Follicles J. Immunol., May 1, 2005; 174(9): 5720 - 5728. [Abstract] [Full Text] [PDF]
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H. Yang, M. Kala, B. G. Scott, E. Goluszko, H. A. Chapman, and P. Christadoss Cathepsin S Is Required for Murine Autoimmune Myasthenia Gravis Pathogenesis J. Immunol., February 1, 2005; 174(3): 1729 - 1737. [Abstract] [Full Text] [PDF]
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A. Q. Khan, A. Lees, and C. M. Snapper Differential Regulation of IgG Anti-Capsular Polysaccharide and Antiprotein Responses to Intact Streptococcus pneumoniae in the Presence of Cognate CD4+ T Cell Help J. Immunol., January 1, 2004; 172(1): 532 - 539. [Abstract] [Full Text] [PDF]
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Z.-Q. Wu, A. Q. Khan, Y. Shen, K. M. Wolcott, W. Dawicki, T. H. Watts, R. S. Mittler, and C. M. Snapper 4-1BB (CD137) Differentially Regulates Murine In Vivo Protein- and Polysaccharide-Specific Immunoglobulin Isotype Responses to Streptococcus pneumoniae Infect. Immun., January 1, 2003; 71(1): 196 - 204. [Abstract] [Full Text] [PDF]
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