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Departments of Medicine and Immunology, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, CO 80262; and
Simmons Arthritis Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75235
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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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Ag can be targeted to other B cell surface receptors, including complement receptors such as CD21. CD21 is a 140-kDa glycoprotein located on the surface of mature B lymphocytes, as well as on follicular dendritic cells, pharyngeal epithelial cells, thymocytes, and some T cells. It binds the terminal products of C3 degradation that have become covalently bound to Ag or immune complexes in the course of complement activation. Studies performed in vivo have confirmed the critical role of CD21 in the generation of a normal humoral immune response. Normal murine Ab responses to T-dependent Ags are inhibited by pretreatment with mAbs to CD21 or soluble CD21 (4, 5, 6). Mice rendered CD21-deficient using gene-targeting techniques demonstrate similar alterations (7, 8). B cell CD21 was found to be critical for these effects based on studies in bone marrow chimeras, in which the immune defects were corrected by reconstitution with bone marrow from CR2+/+ MHC-matched littermates. The role of B cell CD21 was further confirmed in mice created by RAG-2-deficient blastocyst complementation (9). These animals specifically lack CD21 on their B cells, but have normal expression on their follicular dendritic cells (FDC). These studies demonstrated that the targeting of complement-coated immune complexes to FDC is not sufficient for the development of a normal humoral response in the absence of complement receptors on B lymphocytes. Additional studies have supported an adjuvant-like role of complement in B cell responses. C3d linked to hen egg lysozyme (HEL)3 by recombinant DNA techniques was 1,000–10,000 times more immunogenic than HEL alone, inducing enhanced Ca2+ mobilization in vitro as well as augmenting primary and secondary Ab responses in vivo (10).
CD21 may participate in the development of a normal immune response by several mechanisms. First, ligation of CD21 may result in various signals that are critical for normal B cell responses. Previous studies have shown that B cell proliferation and differentiation can be induced by cross-linking CD21 with polymeric C3d or certain anti-CD21 mAbs in the presence of T cell factors (11, 12) or phorbol esters (13). CD21 also plays a synergistic role in the activation of B cells induced by ligation of surface IgM, as measured by calcium mobilization (14), proliferation (15), or induction of c-fos mRNA levels (16). Many of the signaling effects induced by CD21 have been attributed to its physical association with CD19 and CD81 (TAPA-1) on the surface of B lymphocytes (17, 18, 19). Signaling through CD19 has been reported to augment that of soluble IgM, with coligation of the two receptors lowering the threshold for B cell activation by two orders of magnitude (20).
Alternatively, CD21 may participate in the generation of a normal immune response by internalizing and directing C3-bound Ag into the class II processing pathway of B cells. This was first suggested by Lanzavecchia et al. (21) who demonstrated an augmented anti-Ig-specific T cell response to transformed B cells pulsed with anti-CD21 mAbs. Other investigators have utilized C3-linked ligands for CD21 to demonstrate this same phenomenon. In one report, tetanus toxoid was covalently cross-linked to C3b and C4b (22). In a second, immune complexes were generated by incubating normal human serum with keyhole limpet hemocyanin (KLH) linked to a solid phase support (23). In both of these studies, transformed B cells pulsed with complement-containing immune complexes elicited a greater response from Ag-specific T cells as compared with B cells pulsed with Ag or immune complexes lacking complement. We have recently extended these findings by demonstrating that CD21 on transformed B cells mediates the presentation of Ag derived from complement-influenza-anti-influenza IgG immune complexes formed in vitro in a physiologically relevant manner (24). The ability of CD21 to bind complement-coated Ags should enable a much larger number of B cells to participate in Ag presentation, since CD21 is expressed on all mature B cells regardless of their specificity.
Fc receptors have also been demonstrated to play a role in augmenting B cell Ag presentation (25). They would likewise be expected to extend the ability of the nonspecific B cell to participate in Ag presentation. However, previous data from this laboratory suggest that binding of immune complexes to B cells is dependent on the presence of complement in the complexes (24). The lack of immune complex binding in the absence of complement suggests that Fc receptor-mediated Ag presentation plays a less critical role in Ag presentation by nonspecific B cells.
All of the studies to date have analyzed the function of CD21 in augmenting Ag presentation using transformed B cell lines, which constitutively express costimulatory molecules thought to be important in Ag presentation. Resting B cells do not constitutively express these molecules. It is not known whether they function as APCs after binding complement-coated Ag. We wished to address the question of whether targeting Ag to CD21 on resting B cells would result in the generation of sufficient peptide-MHC complexes to elicit a T cell response. In addition, we wished to determine whether ligation of CD21 by complement-immune complexes would result in B cell activation and in the up-regulation of costimulatory molecules important in the generation of a normal T cell response. In the present study, we examined these questions using resting B cells purified from the peripheral blood of human donors. We found that these cells are fully capable of presenting Ag derived from complement-influenza immune complexes to a panel of influenza-specific T cell clones. This process is complement-dependent and likely occurs via CD21. However, CD21 ligation by complement-immune complexes does not result in B cell activation and the induction of well-characterized costimulatory molecules in the absence of T cell help. These data support the hypothesis that CD21 participates in the generation of a normal immune response by its ability to direct Ag into the class II Ag processing pathway, in a process that occurs independently of B cell activation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Polyclonal goat Abs to influenza hemagglutinin (A/Aichi/2/68) were obtained from the National Institute of Allergy and Infectious Diseases Biological Reagent and Reference Repository (anti-H3; Braton Biotech, Rockville, MD). The murine mAbs to CD21 (HB5), CD3 (OKT3), CD14 (63D3), CD16 (B73.1), and CD11b (LM2/1.6.11) were obtained from the American Type Culture Collection (Manassas, VA). Phycoerythrin (PE)-labeled anti-CD19 (B43) was obtained from PharMingen (San Diego, CA). Biotinylated anti-CD19 (B4) was obtained from Coulter (Miami, FL). FITC-labeled anti-CD69 was obtained from Becton Dickinson (Sunnyvale, CA). FITC-labeled CD86 was obtained from The Binding Site (Birmingham, U.K.). Rabbit polyclonal Ab to CD21, Ab73, was generated by immunization with a soluble human CD21 produced by recombinant baculovirus in insect cell culture. It recognizes short consensus repeats 1–2 of CD21 including the C3d binding site (V.M.H., unpublished data). The mouse mAb to CD32, AT10 (26), was the kind gift of Dr. P. M. Morganelli (Veterans Administration Hospital, White River Junction, VT). The mouse mAb to CD35, 3D9, was the kind gift of Dr. Eric Brown (Washington University, St. Louis, MO) (27).
Purification of peripheral blood B lymphocytes
B cells were purified from peripheral blood by either negative or positive selection. For negative selection, PBMCs were depleted of monocytes and NK cells by treatment with 0.09 mg/ml leucine methyl ester for 45 min at room temperature, and subsequently depleted of T cells by rosetting with SRBCs. The remaining population was treated with 10 µg/ml OKT3, 63D3, B73.1, and LM2/1.6.11, followed by labeling with goat anti-mouse magnetic beads (MACS; Miltenyi Biotec, Sunnyvale, CA), and selection for negative cells from a high-gradient magnetic separation column (MACS; Miltenyi Biotec). For positive selection, PBMCs were stained with biotinylated mAb to CD19 (B4) and selected over a Cellprate LC avidin column (Cellpro, Bothell, WA). Cells were analyzed after purification by staining with PE-labeled anti-CD19 (B43; PharMingen, San Diego, CA) and were determined to be 90–98% CD19-positive. The resting state of these cells was confirmed by their lack of expression of CD69 and CD86.
Preparation of immune complexes
Influenza virus HK X-31 (recombinant between A/Aichi/2/68 and A/PR/8/34) was grown in embryonated chicken eggs and live virus purified over a sucrose gradient. Virus was inactivated by UV irradiation. Immune complexes were generated by incubation of inactivated virus with RPMI 1640 and 5% normal human serum from a single donor which contains high titers of influenza-specific IgG (24). Complexes were allowed to form at 37°C for 1 h. Serum samples that were inactivated by heat (56°C for 1 h) or by incubation with methylamine (Sigma, St. Louis, MO) (100 mM, 37°C for 1 h followed by exhaustive dialysis against PBS) were used to generate immune complexes lacking complement. In some experiments, synthetic immune complexes were generated by incubating biotinylated human IgG1 (Sigma) with FITC-streptavidin (Life Technologies, Gaithersburg, MD) for 30 min at 4°C. Either normal human serum or methylamine-inactivated human serum was added to a final concentration of 5% and complement activation allowed to occur at 37°C for 1 h.
Microcytofluorometry assays to analyze immune complex binding
Immune complexes were bound to cells for 30 min at 37°C then washed twice with PBS. They were then analyzed by microcytofluorometry on a FACScan (Becton Dickinson, Sunnyvale, CA). For blocking experiments, blocking Abs were incubated with cells for 30 min at 4°C before the addition of immune complexes. Immune complex binding was detected using goat anti-H3 serum followed by FITC-sheep anti-goat IgG in the case of the influenza-containing complexes, and directly for the IgG/FITC-streptavidin complexes. In experiments involving PBMC populations, B cells were labeled with PE-labeled CD19, and histograms were generated by gating on the CD19-positive cells.
Generation of T cell clones
A panel of influenza-specific human T cell clones was generated from a donor who possesses the MHC class II haplotype: DRB1*0101/DRB1*0401, DQB1*0501/DQB1*0301 (24). T cells were characterized for MHC class II restriction and Ag specificity by testing their IL-2 response to influenza virus or peptide presented by B cell lines and PBMC of known haplotypes (S.A.B., unpublished data). MHC class II restrictions were confirmed by blocking T cell responses with mAbs to class II molecules. Characterization of TCR was performed as described (28). CL19 is restricted by HLA-DR1 and -DR4/Dw4, CL23 and CL58 by HLA-DR1, CL35 by HLA-DQ1, and CL62 by HLA-DRw53. CL19 and CL58 both recognize the immunodominant peptide of hemagglutinin, HA307-319. CL62 recognizes a peptide contained within the influenza nucleoprotein. Identification of the peptide Ags for the other clones has not been completed.
Ag presentation assays
Highly purified peripheral blood B cells or B cell lines were incubated with complement-influenza immune complexes for 4 h at 37°C, washed to remove free immune complexes, then plated with T cells in a 96-well round bottom plate at stimulator:responder ratios from 2:1 to 5:1. T cell clones were washed twice to remove excess IL-2 before plating. In some experiments, peripheral blood B cells were incubated for an additional 20 h before addition of T cells. As shown below, this additional incubation period was found to be critical for the presentation of immune complexes by resting B cells. To test whether Ag processing occurred before contact with T cells, the resting peripheral blood B cells were first incubated with immune complexes for 4 h, washed, then incubated for 20 h at 37°C. The cells were then fixed with 0.75% paraformaldehyde in serum-free medium for 5 min at 37° and then for 1–2 h at 4°C. Ten percent FCS in PBS was added to quench the fixative, and the cells were washed and plated with T cells. In all cases, T cell supernatants were harvested after 24 h at 37° and tested for IL-2 by CTLL-2 bioassay as described (29).
Microcytofluorometry assay to analyze B cell activation and up-regulation of costimulatory molecules
Peripheral blood B lymphocytes were incubated with immune complexes for 4 h, washed, and plated in 96-well round bottom plates at 20,000 cells/well in RPMI 1640 containing 10% heat inactivated human serum (HIHS). After 20 h, T cell clones were added at 20,000 cells/well. Cells were harvested after 24 h, stained with PE-labeled anti-CD19 and FITC-labeled anti-CD69 or CD86, and analyzed by dual color microcytofluorometry. Histograms were generated by gating on the CD19-positive cells.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have previously demonstrated that immune complexes formed under
physiological conditions bind to CD21-transfected fibroblasts and to
transformed B cells in a complement- and CD21-dependent fashion (24).
The following experiments were performed to confirm that binding of
these complexes to peripheral blood B cells occurs in a similar manner.
Immune complexes were formed from either acquired anti-influenza
IgG and purified virus, or biotinylated IgG and streptavidin. The
complexes were exposed to normal or heat- or methylamine-treated serum
then were incubated with PBMCs, and binding to CD19-positive cells was
analyzed by microcytofluorometry. Binding was complement-dependent, as
it did not occur with immune complexes formed in serum in which
complement had been inactivated (Fig. 1
).
Identical results were obtained whether the complexes were formed
between influenza virus and acquired Abs, or between biotinylated IgG
and streptavidin (data not shown).
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RII, CD32,
and little, if any, complement receptor 3 (CD11b/CD18; CR3) (data not
shown). Blocking the binding domains of either CD35 (CR1) or CD21 alone
partially inhibited binding, whereas blocking both CD21 and CD35
simultaneously completely abrogated immune complex binding (Fig. 2). There was no effect on immune complex
binding when the cells were pre-incubated with a blocking mAb to CR3 or
CD32, nor could anti-CD32 enhance the inhibition of complex binding
seen with anti-CD21 alone (data not shown). These data suggest that
fluid-phase activation of complement by soluble immune complexes
generates ligands for both CD35 (C3b and C4b) and CD21 (presumably
iC3b). One particle may have either or both types of ligand. Binding of
complement-containing immune complexes to both complement receptors was
seen, whereas no binding to the B cell Fc receptor could be
demonstrated in mixtures prepared in serum in which complement was
inactivated. Again, identical data were obtained regardless of the type
of immune complex used.
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We and others have shown that CD21 can participate in the presentation of Ag derived from complement-containing immune complexes by transformed B cells. These cells constitutively express the costimulatory molecules CD80 and CD86 and are similar to cells that have been triggered by B cell receptor cross-linking (30). We wished to determine whether resting peripheral blood B cells have a similar capacity for Ag presentation via CD21. Although resting B cells are not thought to be good APCs, ligation of CD21 may augment this ability by enhancing uptake or processing of immune complexes or by providing signals which improve the capacity of the cells to present Ag.
A panel of influenza-specific T cell clones was used to analyze the
ability of resting B cells to present Ag derived from complement-coated
immune complexes. Resting B cells purified from the peripheral blood of
HLA-matched donors were pulsed with complement-influenza immune
complexes for 4 h, then incubated for an additional 20 h
before addition of the T cells. The T cell response was analyzed by
measurement of IL-2 in the cell supernatants after a 24-h incubation.
Significant T cell activation was seen only in response to B cells that
were pulsed with immune complexes containing complement, and not to B
cells pulsed with immune complexes prepared in the absence of
complement (Fig. 3). Fixed B cells were
used to determine whether Ag uptake and processing occurred during the
period when the B cells were cultured alone, or only after coculture
with the T cell clones (Fig. 4). When the
B cells were fixed before addition of the T cell clones, their ability
to activate the T cells was reduced but not ablated. Fixed B cells that
had been pulsed with HA307-319 peptide also had reduced ability to
activate the HA307-319-specific T cell clone, CL58, suggesting that
fixation itself decreases the effectiveness of B cells to act as APCs.
The fixation did not cause the B cells to become nonspecific
stimulators of the T cell clones as CL62 did not produce IL-2 in
response to the peptide-pulsed B cells.
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Peripheral blood B cells are not activated by ligation of CD21
To further analyze the events that occur in the B cell subsequent
to immune complex binding, the induction of the early activation marker
CD69 and the costimulatory molecule CD86 was measured. Resting B cells
were purified from peripheral blood. The resting state of these cells
was confirmed by their lack of expression of CD69 and CD86 at time 0
(data not shown). The cells were pulsed with immune complexes for
4 h and then allowed to incubate at 37°C for an additional
20–44 h. Cells were harvested and stained with FITC-labeled
anti-CD69 or anti-CD86. There was little or no evidence of B
cell activation after a 48-h exposure to immune complexes as measured
by CD69 expression, or of costimulatory molecule up-regulation as
measured by CD86 expression (Fig. 5). In
addition, there was no change in the levels of the adhesion molecules
CD11a/CD18 (LFA-1) or CD58 (LFA-3) or in the costimulatory molecule
CD80 on the B cells (data not shown). Similar results were found with
cells harvested 20 h after being pulsed with immune complexes.
These findings suggest that CD21 ligation by immune complexes does not
result in activation of the B cell as measured by traditional markers.
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Additional experiments were performed to determine the conditions
required for the induction of activation markers and costimulatory
molecules in this system. Peripheral blood B cells were pulsed with
complement-influenza immune complexes for 4 h and allowed to
incubate an additional 20 h before the addition of HLA-matched
influenza-specific T cell clones to the culture. Cells were harvested
after 24 h, stained with anti-CD19 and either anti-CD69 or
anti-CD86, and analyzed by dual color microcytofluorometry. Some
cells were pulsed with HA307-319 peptide as a positive control for T
cell activation and its reciprocal effects on B cell activation. The B
cells that had been pulsed with either immune complexes or HA307-319
peptide before incubation with T cells expressed high levels of CD69
and moderate levels of CD86 on their surface (Fig. 6). This was in contrast to those cells
that had been incubated in medium alone, in that few cells in this
population expressed CD69 and none expressed CD86. These data suggest
that T cell factors are critical in the full activation of resting
peripheral blood B cells, and that these T cell responses are elicited
by the recognition of Ag derived from complement-containing immune
complexes in the absence of B cell activation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The physiological immune complexes formed in these experiments contain acquired anti-influenza IgG. While these data support the role of complement opsonization in B cell Ag presentation following an established humoral immune response, it is likely that other immune complexes can be presented in this manner. Natural Abs directed against a variety of foreign particles are present constitutively and can activate the classical pathway. Furthermore, the alternative pathway of complement activation can be initiated by many microbial pathogens in the absence of specific Ab. We have shown that influenza is opsonized by complement and binds equally well to B cells regardless of whether the complexes are formed by the alternative or the classical pathway of complement activation (data not shown). Since complement-opsonized complexes can be formed in the absence of high titer-specific Ig, CD21-mediated Ag presentation may also play a role in the responses to Ags for which a humoral immune response has not yet been mounted.
Resting peripheral blood B lymphocytes were fully capable of presenting complement-bound Ag to a panel of class II-restricted Ag-specific T cell clones. Interestingly, a longer incubation period before exposure to T cells was required for Ag presentation in resting B cells as compared with transformed B cells. Critical costimulatory molecules expressed constitutively on transformed B cells may need to be up-regulated on resting B cells before they can function as competent APCs. This is an unlikely explanation in this system as the up-regulation of classical costimulatory molecules (CD80/86 and LFA-1/LFA-3) was not induced by incubation with complement-containing complexes, nor do the T cell clones used in these experiments require these molecules for their activation (data not shown). Alternatively, the ability of resting B cells to internalize and process Ag may be less efficient than in transformed B cells. The B cells clearly had processed Ag and targeted specific peptide to their class II molecules in the absence of T cell help, since fixation of the cells after exposure to immune complexes did not ablate their ability to activate the T cells.
Our studies demonstrate that polyclonal B cells participate in Ag presentation in vitro; a recent study using a novel mAb specific for peptide-class II complexes suggests that this process also occurs in vivo (33). After i.v. injection of high titers of soluble HEL, nearly all B cells in lymphoid tissues were found to have HEL 46-61-I-Ak complexes on their surface using a mAb specific for this complex. The mechanism by which these B cells load class II molecules with peptide was not determined, nor was it clarified whether lower amounts of injected Ag resulted in display of peptide by the majority of B cells. Nonetheless, these studies suggested that polyclonal B cells are a major player in the in vivo presentation of Ag, and it is possible that one way in which they participate in this process is by uptake of Ag-C3d complexes by CD21.
The recruitment of T cell help by Ag-nonspecific B cells could result in the polyclonal expansion of B cells and the production of nonspecific Abs. To maintain selectivity of B cell responses, the ability of the B cell to respond to T cell help may be dependent upon coligation of surface Ig and CD21. This is supported by a recent report by Thornton, et al. (34), in which the incubation of PBMC with complement-coated KLH immune complexes resulted in the synthesis of Abs specific for KLH, rather than a polyclonal Ab response. This finding suggests that although CD21 can serve as a vehicle for internalizing Ag, it will not transduce signals which result in the independent production of Ab in the absence of signals through sIg.
The ability of B cells to present Ag in different circumstances is
modeled in Fig. 7. Resting B cells of
diverse antigenic specificities can take up Ag by CD21. Since they do
not express costimulatory molecules, as demonstrated by our studies,
they are not involved in the initial activation of naive T cells
(top row). However, they may be involved in the
continued activation of T cells that have been previously primed by
dendritic cells or activated monocytes (bottom row).
Previously activated T cells are believed to have less stringent
requirements for costimulation. These T cells are initially activated
in the periarteriolar lymphoid sheath (PALS) region of the spleen or
the parafollicular cortex of lymph nodes and subsequently move into the
marginal zone where they come in contact with B cells of multiple
specificities. Ag-specific B cells located in this region which have
bound Ag by IgM alone or in conjunction with CD21 (second and third
rows) can be activated and induced to up-regulate costimulatory
molecules. These cells can participate in cognate B-T interactions with
memory, and perhaps, naive T cells. However, B cells specific for the
Ag of interest would be rare at this stage of the immune response,
whereas all of the B cells would express CD21 and be capable of binding
complement-coated Ag. The participation of these nonspecific
CD21-expressing B cells in stimulating Ag-specific primed T cells would
increase the likelihood that the immune response would be propagated.
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Although our experiments do not support a role for CD21 in regulating
CD86 expression, others have demonstrated that CD21 ligation results in
up-regulation of both CD80 and CD86. One study analyzed the effects of
incubating complement-containing KLH immune complexes with human PBMC
and found that expression of CD80 was induced within 1 h (23).
This effect was thought to be due primarily to FcRII ligation by the
immune complexes, with CD21 ligation playing a synergistic role. A
second investigation analyzed the responses of resting murine splenic B
cells to cross-linking of CD21 with mAbs. In these experiments, the
expression of both CD80 and CD86 was up-regulated within 14 h
(42). There are several potential explanations for the discrepancy
between these results and our own. The first study used unfractionated
B cells, and it is possible that the B cell effect was indirect, being
triggered by another cell population that actually bound the immune
complexes. The results in the second study may result from the use of a
different population of B lymphocytes or an alternative method of
ligating CD21 or from species specific variations in B cell responses.
The studies described in this report support the role of resting B cells in Ag presentation by means of their ability to bind complement-coated Ag to surface complement receptors. The inability of B cells to become fully activated in response to CD21 ligation alone may provide the mechanism by which specific Ab responses are maintained, despite the provision of T cell help. Furthermore, the inability of the B cell to up-regulate CD86 may allow the cell to stimulate previously activated T cells specific for foreign Ags, while tolerizing naive T cells specific for self Ags.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. David R. Karp, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-8884. E-mail address: ;
3 Abbreviations used in this paper: HEL, hen egg lysozyme; KLH, keyhole limpet hemocyanin; PE, phycoerythrin; CR, complement receptor; TAPA-1, target of antiproliferative antibodies-1.
Received for publication June 23, 1998. Accepted for publication August 20, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RII on human B cells can mediate enhanced antigen presentation. Cell. Immunol. 167:188.[Medline]
RII antibody, AT10, and its incorporation into a biospecific F(ab')2 derivative for recruitment of cytotoxic effectors. Mol. Immunol. 28:1243.[Medline]
RIIB1 inhibition of BCR-mediated phosphoinositide hydrolysis and Ca2+ mobilization is integrated by CD19 dephosphorylation. Immunity 7:49.[Medline]
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5000 cpm. Data are
representative of three separate experiments.
