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*
Research Institute for Biological Science, Science University of Tokyo, Noda, Chiba, Japan; and
Departments of Medicine and Immunology, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, CO 80262
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B7-1 (CD80) and B7-2 (CD86) are costimulators that interact with both CD28 and CTLA-4 (CD152) (18, 19). B7-2 is normally expressed at very low levels on splenic B cells and is rapidly up-regulated in vitro within a few hours following sIgM ligation or treatment with activators such as IL-4 or LPS (20, 21). B7-1 is absent from resting B cells, and its expression is also increased following LPS or IL-4 treatment. However, this occurs with much slower kinetics, usually requiring 2 or 3 days for maximal up-regulation, and B7-1 expression is not effectively induced by sIgM ligation alone (21, 22). From these and other studies, it has been suggested that B7-2 would associate with CD28 early after B cell activation to send costimulatory signals to T cells (18), whereas B7-1 may associate with CTLA-4 to send a negative signal that terminates immune responses at a later time point (23, 24). However, unique roles for B7-1 and B7-2 in T cell activation are not definitely established. Other experiments have suggested a possible role for relative B7-1 and B7-2 expression in the determination of Th-1 vs Th-2 responses (25), or of CD8 vs CD4 responses (26).
Both B7-1 and B7-2 have also been shown to play important roles in the formation of germinal centers. For example, treatment with anti-B7-2 mAb results in the lack of germinal center formation following immunization (27). In addition, although B7-1-deficient mice have essentially normal B cell responses, recent studies have shown that in the absence of B7-2 expression, B7-1 is required for the adjuvant-dependent increase in B cell isotype switching and germinal center formation (28). Because of this, a major role for B7-1 in mediating adjuvant-induced costimulation has been proposed (28).
We have previously reported that co-cross-linking of sIgM with CD21/CD35 partially rescues resting splenic B cells and WEHI-231.7 cells from apoptosis induced by sIgM ligation alone (29). The CD21/CD35-derived rescue signal was additive with T cell signals provided by CD40 ligation or IL-4 (29). Herein, we report that co-cross-linking sIgM with CD21/CD35 or cross-linking CD21/CD35 alone also rapidly up-regulates both B7-1 and B7-2 expression on resting B cells. The kinetics of the increased expression is similar for both B7-1 and B7-2. In addition, cross-linking CD19 leads to increased B7-1 and B7-2 expression. A rapid increase in B7-1 is a unique response to CD21/CD35/CD19 complex ligation and distinguishes the results of ligation of these molecules from those of other B cell activators previously reported.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell lines producing rat anti-mouse CD21/CD35 mAb (8D9, IgG2a; 4E3, IgG2a; 7G6, IgG2b; and 7E9, IgG2a) and CD35-specific mAb (8C12, IgG2c) were provided by Dr. Taroh Kinoshita, Osaka University (Osaka, Japan) (30, 31). The cell lines producing rat anti-mouse IgM (b-7-6), rat anti-mouse Thy-1 (T24/40), and mouse anti-mouse Thy-1.2 (HO13) were provided by Dr. John Cambier at the National Jewish Center for Immunology (Denver, CO). The control rat anti-mouse Crry/p65 mAb (1F2) was produced in the laboratory (32). Goat anti-rat IgG Ab, Fc fragment specific, was purchased from Pierce Chemical Co. (Rockford, IL). Biotinylated anti-mouse B7-1 (1G10, 16-10A1) and B7-2 (GL1) mAbs in addition to PE-conjugated anti-B220 mAb (RA3-6B2) were purchased from PharMingen (San Diego, CA). Anti-CD19 mAb 1D3 and rat IgG2a isotype control mAb R35-95 were obtained from PharMingen. Rat anti-mouse B7-1 (RM80), anti-mouse B7-2 (GL1), and anti-mouse class II (M5/114) mAbs in addition to those described above were purified from supernatants using protein G-Sepharose 4 Fast Flow (Pharmacia Biotech, Piscataway, NJ). Purified mAbs were biotinylated by standard methods using N-hydroxysuccinimidobiotin (Sigma Chemical Co., St. Louis, MO) or conjugated with FITC for use in flow cytometric analysis.
Preparation and in vitro treatment of resting splenic B cells
Splenic resting B cells from 5- to 7-wk-old BALB/c (H-2d) mice were prepared as previously described (33). Briefly, after depleting T cells using anti-Thy1 mAbs (HO13 and T24/40) and rabbit complement (Life Technologies, Grand Island, NY), resting B cells (1.079) were isolated by discontinuous Percoll (Pharmacia Biotech, Piscataway, NJ) gradient centrifugation. The purity of cells was 80 to 85%.
Resting B cells (1 x 106/ml) were incubated in 10%
FCS-Iscove’s modified Dulbecco’s medium containing various
combinations, described in the text. To cross-link CD21/CD35 or CD19
molecules, 1 µg/ml of rat anti-CD21/CD35, anti-CD35,
anti-CD19, or control mAb in addition to 5 to 20 µg/ml of goat
anti-rat IgG, Fc fragment-specific (Pierce) Ab (designated
secondary Ab herein) were used. To cross-link sIgM, 1 µg/ml of rat
anti-mouse IgM (b-7-6) and the same secondary Ab were incubated
together. Co-cross-linking experiments included 1 µg/ml of each of
the indicated primary mAbs in addition to the same secondary Ab. Other
conditions included 300 U/ml of mouse IL-4 (Genzyme, Cambridge, MA),
0.1 vol of CD40L-containing supernatant from mCD40L-mCD8
transfected
J558L cells (34), or 50 µg/ml of LPS, Escherichia coli
serotype 055:B5 (Difco Laboratories, Detroit, MI).
All reagents used were analyzed for endotoxin (Limulus amebocyte lysate HS-F, Wako, Osaka, Japan) and, if necessary, absorbed over Polymyxin B-Sepharose (Sigma Chemical Co.).
Flow cytometric analysis
After washing with 1% BSA/PBS/0.1% NaN3
twice, 1 x 106 cells/condition were stained using
either FITC- or PE-conjugated mAbs or biotinylated mAb followed by
washing and then streptavidin-FITC (Southern Biotechnology Associates,
Birmingham, AL). To minimize nonspecific staining, 10 µg of
anti-Fc
RII-specific mAb 2.4G2 was added to each staining step.
Cells were then analyzed by FACSort (Becton Dickinson, Palo Alto, CA)
or Coulter EPICS XL (Irving, TX). Ten thousand cells were examined per
sample and were analyzed by CellQuest (Becton Dickinson Immunocytometry
Systems, Mansfield, MA).
Allogeneic MLR
Responder T cells were prepared from inguinal, brachial, axial, cervical, and mesenteric lymph nodes of C57BL/6 (H-2b) mice (6–24 wk old) by negative panning using affinity-purified goat anti-mouse IgG (heavy and light chains) Abs (Rockland, Gilbertsville, PA). The purity of T cells was 90 to 95%. For allogeneic MLR, BALB/c B cells that had been treated for 18 h under the different conditions described above were washed and then either gamma irradiated (500–1000 rad) or used without further manipulation. B cells (3.6–6 x 105) were incubated for 2 to 6 days in triplicate alone or with 1.8 to 6 x 105 freshly isolated T cells in 200 µl using 96-well plates. Individual wells were pulsed with 0.25 µCi/well [3H]TdR for the last 16 h of culture, harvested through Printed Filtermat A (Wallac, Turku, Finland), and counted using a 1205 Betaplate TM counter (Pharmacia/LKB, Piscataway, NJ) or a 1450 MicroBeta Trilux (Wallac, Turku, Finland).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have previously shown that co-cross-linking sIgM with CD21/CD35
using mAbs rescues resting splenic B cells from apoptosis induced by
sIgM ligation alone (29). To further extend this study, we examined
whether cross-linking CD21/CD35 would alter other important B cell
phenotypes such as costimulatory molecule expression, and also compared
the CD21/CD35-induced changes to those mediated by other activators. As
shown in Figure 1
A, similar to
previous reports (22), B7-1 expression was not significantly increased
when sIgM was ligated for only 15 h. In contrast, significant B7-1
expression was observed following CD21/CD35 cross-linking alone at this
time point (Fig. 1B). B7-2 expression was also
significantly increased following CD21/CD35 cross-linking alone (Fig. 1E).
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C) and B7-2
(Fig. 1F) phenotype compared with that of cells
cross-linked with sIgM alone (Fig. 1, A and
D). Although in this experiment there was a decrease
in B7-1 and B7-2 expression following co-cross-linking of both
molecules compared with cross-linking CD21/CD35 alone, we believe that
this is due to minor experimental differences or the relative amounts
of mAbs used in the co-cross-linking experiments. In other experiments
(see Fig. 3 below) levels were not decreased by co-cross-linking, and
when we increased the amount of Abs used in the co-cross-linking by
twofold, the levels returned to those induced by CD21/CD35
cross-linking alone (data not shown).
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, staining with another mAb,
anti-Thy-1.2, did not demonstrate significantly enhanced reactivity
following CD21/CD35 cross-linking alone or co-cross-linking with sIgM.
Anti-CD3 staining was also not significantly altered (data not shown).
In addition, expression of other cell surface Ags such as CD2, B220,
and Crry/p65, a widely distributed complement regulatory protein, did
not change, as assessed by flow cytometry following CD21/CD35
cross-linking (data not shown). From these results, we conclude that
expression of B7-1 and B7-2 is specifically altered by CD21/CD35
cross-linking.
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We have also measured the kinetics of B7-1 and B7-2 expression
following CD21/CD35 cross-linking compared with other B cell activators
known to regulate levels of these proteins. Consistent with previous
reports (22), as shown in Figure 3,
following treatment of resting B cells with LPS, B7-1 expression
increased slowly over 2 or 3 days, while B7-2 expression increased very
rapidly. Following sIgM cross-linking, B7-1 levels did not markedly
change in this population; however, B7-2 expression rapidly increased
beginning at early time points within the first 24 h. In contrast
to these other activators, cross-linking CD21/CD35 alone and
co-cross-linking sIgM with CD21/CD35 resulted in markedly increased
B7-1 expression that peaked between 14 and 24 h. Similar kinetics
were found when analyzing B7-2 expression following CD21/CD35
cross-linking with or without co-cross-linking of sIgM.
Treatment of B cells with other activators, including IL-4 and mCD40L, also markedly increased B7-2, but not B7-1, expression at 15 to 18 h (data not shown). Our results using IL-4, mCD40L, and LPS are similar to those of previous reports, and it is apparent, therefore, that substantial B7-1 expression at early time points is a unique response to CD21/CD35 cross-linking.
Effects of other mAbs recognizing CD21/CD35 or CD35 alone on B7-1 and B7-2 expression
In mice, CD21 is expressed as an alternative transcript along with CD35 from the Cr2 gene, and most, if not all, splenic B cells appear to express both proteins (37, 38). Because the carboxyl-terminal two-thirds of the mouse CD35 protein is identical with CD21, including the transmembrane and intracytoplasmic sequences, it has been assumed that the signal transduction events mediated by ligation of each receptor are identical. In the experiments described above, we used the rat anti-CD21/CD35 mAb 7E9 to cross-link CD21/CD35 complexes. We have also analyzed B7 expression following treatment with other mAbs (8D9, 4E3, and 7G6) that, like 7E9, recognize both CD21 and CD35 or, in the case of mAb 8C12, recognize only the longer CD35 molecule. Each of the mAbs we have tested recognizes a unique epitope (39).
As shown in Figure 4, two of the five
mAbs have clearly demonstrable effects on B7-1 and B7-2 expression.
Treatment with the anti-CD21/CD35 mAb 4E3 is also capable of
markedly enhancing expression of both B7-1 and B7-2. In this
experiment, cross-linking with mAb 7E9 or 4E3 alone resulted in a mean
channel fluorescence (MCF) for B7-1 expression of 110 and 68.2,
respectively (Fig. 4, lower left). Sixty-one and
sixty percent of the cells specifically stained with the anti-B7-1
mAb following cross-linking with 7E9 and 4E3, respectively (data not
shown). Both mAbs also mediated increased B7-1 expression when
co-cross-linked with sIgM (Fig. 4, upper left).
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There is no clear relationship between the ability of a mAb to block C3 binding to mouse CD21 and/or CD35 and the up-regulation of B7-1 and B7-2. For example, mAb 7E9, which does not block C3 binding, mediates increased B7 expression, whereas mAb 7G6, which blocks C3d binding, does not. On the other hand, mAb 4E3, which also blocks C3d binding but recognizes a different epitope than 7G6 within the C3d-binding domain (39), does mediate increased B7 expression to a comparable level as 7E9. Although the reason for the lack of correlation is not known, this result is similar to that found when studying human CD21. In this setting, anti-human CD21 mAb HB5, which does not recognize the C3d binding domain and does not block ligand binding, has been extensively used in B cell signaling experiments to demonstrate CD21-mediated enhancement (6, 7).
Effect of CD21 cross-linking on the allogeneic MLR
We next wanted to determine whether this early increase in B7-1 and B7-2 expression following CD21/CD35 cross-linking with or without sIgM could be detected in a functional manner by responding T cells. To study the effect of up-regulation of both B7-1 and B7-2 expression at the same time on B cells, we used the allogeneic MLR as a model. This allowed us to minimize the potential effects of CD21/CD35 ligation on Ag uptake and processing. In addition, we studied both the two-way and one-way MLR to be able to measure effects on both B and T cell proliferation.
Figure 5 demonstrates the specific
CD21/CD35-mediated effects on a two-way allogeneic MLR analyzed on day
2. As shown, co-cross-linking of sIgM with the control mAb (recognizing
Crry/p65) on B cells slightly increased proliferation at the higher T
cell dose. This increase with control mAb is probably due to
sIgM-mediated effects, as cross-linking sIgM alone in other experiments
resulted in a similar increase (data not shown). In comparison,
however, co-cross-linking of sIgM with CD21/CD35 resulted in the
highest levels of proliferation, demonstrating that CD21/CD35
specifically enhances B and/or T cell activation in this system.
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, the major effect of CD21/CD35 is an
enhanced T cell proliferative response to irradiated B cells upon which
CD21/CD35 had been co-cross-linked with sIgM. Although seen on day 2,
the CD21/CD35-related effects are most pronounced after 4 days of
culture.
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Effect of anti-B7-1 and anti-B7-2 mAbs on the CD21/CD35-enhanced allogeneic MLR
To determine whether the enhanced effect of CD21/CD35
co-cross-linking with sIgM in the MLR was dependent on the
up-regulation of B7-2 and/or B7-1 or potentially used another
costimulatory mechanism, we cultured -irradiated B cells and fresh T
cells in the presence of blocking anti-B7 mAbs. As controls, the
allogeneic MLR, with or without CD21/CD35 enhancement, was suppressed
by anti-CD4 and anti-class II mAbs (data not shown). In
addition, as shown in Figure 7,
anti-B7-2 treatment blocked the proliferation of T cells almost
completely for every condition, including co-cross-linking of CD21 with
sIgM, whereas anti-B7-1 treatment partially blocked proliferation.
This pattern demonstrating a dominant costimulatory effect of B7-2 and
a lesser, but clearly detectable, B7-1 component is similar to that
recently reported when studying T cell activation requirements in mice
in which the B7-1 and/or B7-2 genes have been inactivated (41). It
appears, therefore, that CD21/CD35 coligation with sIgM costimulates T
cells using the same mechanism as other B cell activators, and that
both B7-1 and B7-2 can act in concert to activate or regulate responder
T cells following CD21/CD35 ligation.
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CD19 cross-linking also leads to increased B7-1 and B7-2 expression
Because mouse CD19 has been shown to associate with CD21/CD35, and
knockouts of both genes demonstrate similar phenotypes, we also
determined whether CD19 cross-linking would lead to increased B7
expression. As shown in Figure 8, CD19
cross-linking does lead to increased B7-1 and B7-2 expression to a
similar level as CD21/CD35. Cross-linking with isotype control IgG2a
mAb had no effect on B7 expression. Therefore, ligation of two members
of the CD21/CD35/CD19 complex can lead to the same increase in B7
molecules. We also found that co-cross-linking of CD19 with sIgM lead
to a similar increase in both B7-1 and B7-2 expression compared with
cross-linking CD19 alone (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We hypothesize that our activation system mimics the effects of C3d-bound Ag that cross-links CD21/CD35 with sIgM. Our observation may thus be able to help explain why CD21/CD35- and CD19-deficient mice have an impaired response to T-dependent Ags (10, 11, 12, 13). In this situation the binding of Ag alone to B cells in the absence of a CD21/CD35/CD19-initiated signal could result in a number of defects. One could be due to the impaired enhancement of sIgM-mediated signaling resulting in a relative decrease in proliferation and differentiation as previously proposed (42). The second, perhaps mediated by similar signaling pathways as the first, is the lack of up-regulation of B7-1 and B7-2 molecules that is a direct consequence of CD21/CD35/CD19 ligation. This relative lack of B7-1 and B7-2 could also lead to ineffective T cell costimulation and a secondary B cell defect.
The results may also help to explain why recombinant HEL-C3d polymers induced an immune response in vivo at a dose at least 1000-fold lower than HEL alone (16), as the "adjuvant" effect of C3d in the HEL polymer may be due in part to the ability to up-regulate B7-1 and/or B7-2. Our proposal that B7 up-regulation by CD21/CD35 cross-linking is an important effect is also consistent with results demonstrating that CD21/CD35-deficient mice manifest defects in the immune response that can be overcome by the use of adjuvant (12). The defect manifest by CD21/CD35 or C3 deficiency also bears features similar to those found when using anti-B7-2 mAb to block germinal center formation in vivo or when studying B cell responses in mice in which the genes encoding B7-1 and/or B7-2 have been inactivated.
It is not clear yet how B7-1 and B7-2 are up-regulated by CD21/CD35 or CD19 ligation, or whether increased expression following CD21/CD35 cross-linking alone is due to CD19-mediated signaling, a novel CD21/CD35-activated pathway, or a cooperative signaling mechanism requiring all three molecules. It is known that CD19 physically associates with CD21 in the cell membrane, and that CD19 is activated following sIgM cross-linking. CD19 can recruit phosphatidylinositol 3-kinase (43, 44, 45) or Vav (46), which regulates Ras or Rac. Co-cross-linking of mouse CD19 and sIgM increases MAP kinase (ERK2, JNK, and p38) activity to a greater extent than cross-linking sIgM alone (47). Thus, a CD19-mediated signaling mechanism that is engaged by CD21/CD35 cross-linking may be important to up-regulate B7 molecules.
In addition, although the most effective enhancement of signaling events mediated by CD19 were shown to follow co-cross-linking with sIgM, increases in p38 activity were found with CD19 ligation alone (47). Of interest, CD40 ligation also activates MAP kinases, especially JNK and p38, in addition to leading to increases in B7-2 expression (48, 49, 50, 51), while sIgM ligation preferentially activates ERK2 (52, 53). By analogy, MAP kinase activation is likely to be involved in the up-regulation of B7-1 and B7-2 expression by the CD21/CD35/CD19 complex.
However, it is still possible that the increase in B7 levels is dependent on CD21/CD35 function alone. First, CD21/CD35 ligation alone efficiently up-regulates both B7-1 and B7-2 in this system, even if sIgM and CD19 are not directly ligated. Second, Luxenbourg et al. have shown that human CD21 ligation alone will engage a homotypic adhesion pathway on primary B cells and B cell lines (54). And third, CD21 is expressed on cell types that do not express CD19, and ligation of CD21 on CD19 negative human T cells results in the formation of an apparently novel cell surface protein complex (55). Further analysis using CD21/CD35- and CD19-deficient mice is necessary to determine the specific mechanisms used to regulate B7-1 and B7-2.
It is also unclear how the phenotype we have described in mice is
related to previous studies of the role of CD21 in human T cell
activation. Human CD21 has previously been shown to mediate increased
Ag presentation by B cell APCs to Ag-specific T cells through a
mechanism that has been believed to involve receptor binding and uptake
(56, 57, 58, 59). Although B7-1 expression on human B cells was studied in one
model (57, 59), its relevance and that of B7-2, especially compared
with the independent effects of human CD21 on Ag binding and uptake,
were not clearly distinguished. In addition, it was hypothesized in
that study that simultaneous CD21 and FcRII (CD32) binding on human
B cells mediated enhanced B7-1 expression. In the other studies (56, 58), B-7 expression was not evaluated. In contrast, in mice that have
been treated with anti-CD21/CD35 mAb (60) and in the
CD21/CD35-deficient mouse (13), T cell priming and the ability to
provide help following T-dependent Ag immunization were not found to be
altered using adoptive transfer techniques.
It is also possible that the increased B7-1 and B7-2 expression mediated by CD21 primarily affects endogenous B cell activation through B7-mediated signal transduction events, a hypothesis that has been previously presented (61). Indeed, recent studies have suggested that human B cell activation is enhanced by anti-B7-2 mAb (62). Interestingly, this increase in activation is seen in a model of CD23-mediated enhancement of IgE synthesis that is a result of CD23 binding to human CD21 in the presence of IL-4 and CD40L. Clearly further analysis is necessary to understand these specific issues.
B7-1 and B7-2 have been hypothesized to manifest differential effects on lymphocyte activation. Therefore, we examined several additional features following CD21/CD35-mediated enhanced expression of these molecules. Specifically, we studied the ability of B cells upon which CD21/CD35 and sIgM had been co-cross-linked (thus expressing both B7-1 and B7-2), compared with sIgM cross-linking alone (expressing B7-2 alone), to secrete differential IgG isotypes in an allogeneic MLR, or, using OVA peptide and T cells from the OVA TCR transgenic DO11 (63), to manifest Th1 vs Th2 dissociation, with or without adding exogenous IL-4 or CD40L. No differences were found in any of these analyses (data not shown). We also examined, using the allogeneic MLR system described above, whether B7-2 more effectively costimulates CD4+ T cells and B7-1 more effectively costimulates CD8+T cells, but again found no differences (data not shown).
Finally, it is interesting to consider why B7 molecules are up-regulated with similar and rapid kinetics following CD21/CD35 ligation. We believe this is so because the immune response is poised to efficiently respond to infection by pathogens (17). When complement is activated on a viral or bacterial Ag by the classical and/or alternative pathway, this target is marked as foreign. In addition, complement can identify many infectious organisms as non-self via the alternative pathway without using Ab (64). C3-bound Ag will then co-cross-link Ag-specific sIgM with CD21 on a subset of B cells. It would make teleologic sense if this co-cross-linking should result in a rapid initiation of the immune response that involved costimulator expression and potentially rapid recruitment of T cell help. This CD21/CD35-mediated response would complement that induced by LPS, a product of many infectious organisms, which also activates B cells to express B7 molecules. Indeed, p38 was found to be the major tyrosine-phosphorylated protein following LPS treatment (65). However, the CD21/CD35 effect is different in that B7-1 expression occurs relatively late following LPS stimulation compared with rapidly following CD21/CD35. This hypothesis is also consistent with recent results using single and double B7-1 and B7-2 knockout mice, which demonstrated unique, but necessary, roles for each protein in B cell responses and germinal center formation (41) and suggest that altered B7 expression may underlie part of the defects seen in mice in which CD21/CD35 and CD19 expression has been eliminated.
In summary, previous studies using inhibitors and knockouts have shown that the CD21/CD35/CD19 complex plays an important role in the initiation and amplification of the cellular immune response. We propose that regulation of B7-1 and B7-2 expression is an important function of the CD21/CD35/CD19 complex. In particular, the ability to mediate rapid increases in B7-1 expression may allow this receptor complex to make a unique contribution to the immune response.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. V. Michael Holers, Division of Rheumatology, B-115, University of Colorado Health Sciences Center, 4200 E. 9th Ave., Denver, CO 80262. E-mail address:
3 Abbreviations used in this paper: sIgM, surface IgM; HEL, hen egg lysozyme; PE, phycoerythrin; CD40L, CD40 ligand; mCD40L, mouse CD40 ligand; MAP, mitogen-activated protein; MCF, mean channel fluorescence.
Received for publication May 20, 1997. Accepted for publication October 23, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A. Malaspina, S. Moir, S. Kottilil, C. W. Hallahan, L. A. Ehler, S. Liu, M. A. Planta, T.-W. Chun, and A. S. Fauci Deleterious Effect of HIV-1 Plasma Viremia on B Cell Costimulatory Function J. Immunol., June 15, 2003; 170(12): 5965 - 5972. [Abstract] [Full Text] [PDF]
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 C. S. Schmidt, J. Liu, T. Zhang, H. Y. Song, G. Sandusky, K. Mintze, R. J. Benschop, A. Glasebrook, D. D. Yang, and S. Na Enhanced B Cell Expansion, Survival, and Humoral Responses by Targeting Death Receptor 6 J. Exp. Med., January 6, 2003; 197(1): 51 - 62. [Abstract] [Full Text] [PDF]
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S. M. Knoetig, T. A. Torrey, Z. Naghashfar, T. McCarty, and H. C. Morse III CD19 Signaling Pathways Play a Major Role for Murine AIDS Induction and Progression J. Immunol., November 15, 2002; 169(10): 5607 - 5614. [Abstract] [Full Text] [PDF]
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A. Mencacci, C. Montagnoli, A. Bacci, E. Cenci, L. Pitzurra, A. Spreca, M. Kopf, A. H. Sharpe, and L. Romani CD80+Gr-1+ Myeloid Cells Inhibit Development of Antifungal Th1 Immunity in Mice with Candidiasis J. Immunol., September 15, 2002; 169(6): 3180 - 3190. [Abstract] [Full Text] [PDF]
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 C. H. Nielsen and R. G. Q. Leslie Complement's participation in acquired immunity J. Leukoc. Biol., August 1, 2002; 72(2): 249 - 261. [Abstract] [Full Text] [PDF]
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A. P. Kohm, A. Mozaffarian, and V. M. Sanders B Cell Receptor- and {beta}2-Adrenergic Receptor-Induced Regulation of B7-2 (CD86) Expression in B Cells J. Immunol., June 15, 2002; 168(12): 6314 - 6322. [Abstract] [Full Text] [PDF]
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A. Cherukuri, P. C. Cheng, and S. K. Pierce The Role of the CD19/CD21 Complex in B Cell Processing and Presentation of Complement-Tagged Antigens J. Immunol., July 1, 2001; 167(1): 163 - 172. [Abstract] [Full Text] [PDF]
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 S. T. Test, J. Mitsuyoshi, C. C. Connolly, and A. H. Lucas Increased Immunogenicity and Induction of Class Switching by Conjugation of Complement C3d to Pneumococcal Serotype 14 Capsular Polysaccharide Infect. Immun., May 1, 2001; 69(5): 3031 - 3040. [Abstract] [Full Text] [PDF]
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J. L. Gommerman, D. Y. Oh, X. Zhou, T. F. Tedder, M. Maurer, S. J. Galli, and M. C. Carroll A Role for CD21/CD35 and CD19 in Responses to Acute Septic Peritonitis: A Potential Mechanism for Mast Cell Activation J. Immunol., December 15, 2000; 165(12): 6915 - 6921. [Abstract] [Full Text] [PDF]
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E. Fernandez-Centeno, G. de Ojeda, J. M. Rojo, and P. Portoles Crry/p65, a Membrane Complement Regulatory Protein, Has Costimulatory Properties on Mouse T Cells J. Immunol., May 1, 2000; 164(9): 4533 - 4542. [Abstract] [Full Text] [PDF]
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 M. W. Hess, M. G. Schwendinger, E.-L. Eskelinen, K. Pfaller, M. Pavelka, M. P. Dierich, and W. M. Prodinger Tracing uptake of C3dg-conjugated antigen into B cells via complement receptor type 2 (CR2, CD21) Blood, April 15, 2000; 95(8): 2617 - 2623. [Abstract] [Full Text] [PDF]
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A. M. Oliver, F. Martin, and J. F. Kearney IgMhighCD21high Lymphocytes Enriched in the Splenic Marginal Zone Generate Effector Cells More Rapidly Than the Bulk of Follicular B Cells J. Immunol., June 15, 1999; 162(12): 7198 - 7207. [Abstract] [Full Text] [PDF]
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D. C. Baiu, J. Prechl, A. Tchorbanov, H. D. Molina, A. Erdei, A. Sulica, P. J. A. Capel, and W. L. W. Hazenbos Modulation of the Humoral Immune Response by Antibody-Mediated Antigen Targeting to Complement Receptors and Fc Receptors J. Immunol., March 15, 1999; 162(6): 3125 - 3130. [Abstract] [Full Text] [PDF]
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S. A. Boackle, M. A. Morris, V. M. Holers, and D. R. Karp Complement Opsonization Is Required for Presentation of Immune Complexes by Resting Peripheral Blood B Cells J. Immunol., December 15, 1998; 161(12): 6537 - 6543. [Abstract] [Full Text] [PDF]
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X. Li and R. H. Carter Convergence of CD19 and B Cell Antigen Receptor Signals at MEK1 in the ERK2 Activation Cascade J. Immunol., December 1, 1998; 161(11): 5901 - 5908. [Abstract] [Full Text] [PDF]
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