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Section of Rheumatology and Departments of
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Medicine and
Pathology, Committee on Immunology, University of Chicago, Chicago, IL 60637
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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and Ig-ß. The cytoplasmic
domains of these latter structures translate Ag engagement into
cytoplasmic signaling events (1, 2). The receptor is activated by
aggregation, which induces the juxtaposition of receptor-associated
kinases, thereby initiating their transphosphorylation
and activation. Among the immediate substrates
phosphorylated are the conserved tyrosines found in the
immunoreceptor tyrosine-based activation motif (ITAM) imbedded in the
cytoplasmic tails of both Ig- and Ig-ß (3). These phosphotyrosines
become the recruitment and activation sites for Fyn (4), Syk (5, 6),
and possibly other tyrosine kinases. The proximal activation of kinases
initiates divergent and interconnecting signaling cascades, of which
the constituents include Erk, phospholipase C, Ras, and
phosphatidylinositol 3 (PI 3)-kinase (7). In the periphery, the
activation of these cascades can drive B cell proliferation,
up-regulate surface activation markers, and increase Ab synthesis
(8). However, for Ig isotype switching, affinity maturation, and the generation of B cell memory, the signals generated by the BCR are not sufficient. T cell-derived lymphokines and surface ligands are also required (9). These costimulatory factors are provided by T cells capable of responding to MHC class II-restricted peptides displayed on the surface of Ag-stimulated B cells (10). The BCR facilitates formation of these MHC class II/peptide surface complexes by endocytosing and delivering Ag to compartments within the cell, where it is processed and loaded onto MHC class II (11, 12, 13). Although controversial, most studies have identified the site of peptide processing as specialized vesicles derived from late endosomes/early lysosomes (MIIC) which bear the marker designated lysosome-associated membrane protein (lamp-1) (14, 15). However, some Ags may be processed in vesicles that lie earlier in the endocytic pathway (16, 17).
Signals delivered by the BCR may also enhance the recruitment of T cell help. Polyvalent Ags are presented up to 50 times more efficiently than monovalent Ags, and this enhancement is not due to differences in internalization, subcellular targeting, or the up-regulation of costimulatory activity (18, 19, 20). Rather, it may be due to an increase in the degradation of endocytosed Ags (20). Although the mechanism by which this occurs is unclear, the observation that BCR ligation induces tyrosine phosphoproteins and GTP-binding proteins to associate with the MIIC (21) indicates that the site of Ag processing might be directly regulated by BCR initiated signaling cascades.
Herein, we report that signals emanating from the BCR induce the redistribution, fusion, and acidification of lamp-1+ endosomal vesicles to form an acidic perinuclear complex containing a majority of the detectable MHC class II within the cytoplasm. These data indicate that the signaling capacities of the BCR may enhance the presentation of Ag by regulating the subcellular compartment in which processing and MHC class II loading occurs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The A20/IIA1.6 B cell line was maintained in Iscove’s modified Dulbecco’s medium (IMDM) (Life Technologies, Grand Island, NY) supplemented with 10% FCS (HyClone, Logan, UT), 2 mM glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin at 37°C in 7.5% CO2.
Rabbit antisera (ABCYTB) was raised against a peptide (CQKGPRGPPPAGLLQ) from the cytoplasmic tail of the mouse MHC class II ß-chain. ID4B and In-1 were provided by Andrea Sant (University of Chicago). The following Abs were purchased: FITC-conjugated anti-goat IgG, FITC-conjugated goat anti-rat IgG, phycoerythrin (PE)-conjugated donkey anti-rat IgG, FITC-conjugated donkey anti-rabbit IgG, rabbit anti-mouse IgG, and rat anti-goat IgG (all from Jackson ImmunoResearch, West Grove, PA); goat anti-mouse IgG2a and biotinylated goat anti-mouse IgG2a (Southern Biotechnology Birmingham, AL); FITC-conjugated anti-rat IgG2b and biotinylated anti-rat IgG2a (Binding Site, Birmingham, U.K.); 15-nm gold-conjugated goat anti-rat IgG and 5-nm gold-conjugated rabbit anti-goat IgG (British Biocell International, Cardiff, U.K.); goat anti-rat IgG (H+L) (ICN, Costa Mesa, CA); and rabbit anti-horse ferritin (Sigma, St. Louis, MO).
Confocal microscopy
For BCR/lamp-1 costaining, A20/IIA1.6 cells were first
incubated with 10 µg/ml goat anti-mouse IgG2a (BCR) Abs at
4°C for 10 min, washed, then incubated with anti-goat IgG-FITC
(1:100) and washed again. Cells were then warmed to 37°C for 0, 15,
or 30 min, fixed with 3% paraformaldehyde/3% sucrose, and
permeabilized with 0.05% saponin essentially as described (22).
Samples were then incubated with ID4B for 1 h at room temperature,
washed, and then incubated with anti-rat IgG-PE (1:100). To label
cells with ferritin, they were washed in ice-cold serum-free IMDM,
resuspended with 0.25 mg/ml cationized ferritin (Sigma) in IMDM, and
incubated on ice for 10 min. Cells were then warmed to 37°C for 30
min, washed, and then resuspended on ice. Following sequential
incubation with goat anti-mouse IgG2a and donkey anti-goat
IgG-FITC, cells were warmed to 37°C for 30 min, then washed, fixed,
and stained with anti-ferritin Abs followed by anti-rabbit-FITC
Abs. Acidic compartments were visualized by incubating samples with 500
nM Lysosensor dye (Molecular Probes, Eugene, OR) at 37°C for 1
h. To stain for invariant chain (Ii), samples were pretreated with 400
µg/ml leupeptin for 2 h before stimulation. Confocal sections of
approximately 0.75 to 1.0 µm were acquired using a Zeiss 410 confocal
microscope and displayed by pseudocoloring using LSM software (Zeiss,
Oberkochen, Germany). All experiments were performed at least three
times by two investigators working independently (K.S. and B.J.E.).
To test for inhibition of lamp-1+ vesicle aggregation
formation, cells were treated with genistein (Life Technologies) for 15
min at 100 µg/ml, wortmannin (Sigma) for 10 min at 1 µM, or
staurosporin for 12 h at 1 µM (Calbiochem, San Diego, CA) before
BCR cross-linking with 10 µg/ml anti-mouse IgG2a. Induction of
vesicle activation without receptor engagement was tested by
stimulating cells with 10 ng/ml PMA, 1 µM ionomycin, or both together
for 15 min at 37°C. Induction of aggregation was quantitated by
scoring 10 random confocally scanned fields (
100 cells).
Electron microscopy
Cells were stimulated for 15 min with anti-IgG, as described above, or with rabbit anti-IgG (10 µg/ml), followed by 5-nm gold particle-conjugated donkey anti-rabbit IgG (1:4 dilution), then fixed in 8% formaldehyde/250 mM HEPES, pH 7.2. Cells were infiltrated with 2.3 M sucrose, frozen in liquid nitrogen, and sectioned at -110°C. For immunostaining, samples were blocked in 10% FCS/0.12% glycine/PBS at room temperature for 30 min, then incubated with ID4B at a 1:2 dilution for 30 min, and then washed two times in PBS/0.12% glycine. Samples were then incubated with 15-nm gold particle-conjugated-goat anti-rat IgG. After washing with PBS/glycine and distilled water, the grids were incubated with a 1.8% methyl cellulose/0.3% uranyl acetate solution. Samples were visualized using a JEOL 100 CX transmission electron microscope (JOEL, Peabody, MA) at an accelerating voltage of 60 kV (23).
Estimation of the distribution vesicle size
Random sequential images from ID4B-stained electron microscopic
samples, which contained lamp-1+ structures with
discernible membranes, were printed at a final magnification of
x21,000. The long (l) and short (s) diameter of each
lamp-1+ vesicle was measured in mm, and the relative volume
of each was estimated by the equation [(l +
s)/2]3
. Fifty vesicles were quantitated in the
unstimulated group and 100 in the stimulated group.
Stereology
From two grids for each sample, a typical field of cells was
selected. A sequential and contiguous series of photomicrographs
(x34,000, final magnification) was obtained (75 per series, 300
total), which encompassed the field within the relevant grid space.
Given that the orientation of cells sampled was random and therefore
isotropic, volume estimations of the lamp-1+-staining
vesicles and of the total cell were determined by point counting. To
determine the surface area of the lamp-1+ vesicles, test
line intersections crossing the positive-staining vesicle membrane were
counted, and the ratio of the lamp-1+ vesicle surface area
to the total cell volume was determined (23).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The murine B cell line A20 IIA1.6, which lacks Fc
RII (25), was
stimulated with FITC-conjugated polyclonal anti-IgG Abs for various
times at 37°C, then fixed, permeabilized, and stained with Abs to the
late endosome/lysosome marker, lamp-1 (ID4B) (14, 26). As shown in
Figure 1
A (upper
panels), unstimulated cells had several small
lamp-1-bearing vesicles (red) distributed throughout the cytoplasm.
Following ligation of the BCR, there was a remarkable redistribution of
these vesicles such that by 15 min they formed a single large
perinuclear aggregate in 40 to 50% of the cells, which contained 80%
or more of the lamp-1+ vesicles. These aggregates became
the primary target for the endocytosed ligated BCR complexes
(colocalization shown in yellow). The coalescence of
lamp-1+ vesicles began as early as 5 min and preceded the
arrival of detectable amounts of endocytosed BCR complexes (data not
shown) indicating that coalescence was not occurring in response to the
delivery of endocytosed complexes. Furthermore, the aggregation of
vesicles persisted for at least 4 h, during which time the
aggregate contained the majority of detectable BCR complexes in the
cell (data not shown).
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A (middle panels), although the
TfR complex was internalized efficiently and colocalized with some of
the lamp-1 vesicles (arrow), it did not induce their coalescence. These
data indicate that the simple delivery of an aggregated receptor to the
lamp-1-bearing compartment is not sufficient to induce its
coalescence.
Since the expression of lamp-1 is restricted to late endosomes and
lysosomes, we next asked whether other compartments were responsive to
BCR ligation. Therefore, we first labeled the entire endocytic pathway
in A20IIA1.6 cells with cationized ferritin and then stained
unstimulated and stimulated populations with anti-ferritin and
anti-lamp-1 Abs. As seen in Figure 1A
(bottom panels), the lamp-1+
vesicles constituted only 25 to 50% of the endosomes in resting
cells. Upon stimulation, only the
lamp-1+/ferritin+ subpopulation of vesicles
aggregated, indicating that early endosomes are not responsive to BCR
perturbation. Similar results were obtained when samples were stained
for the early endosomal marker, TfR (data not shown). These data
demonstrate that the BCR responsive compartment is restricted to late
endosomes/lysosomes and that these vesicles are part of the normal
endocytic pathway.
The extinguishing of anti-Ig-FITC and anti-lamp-1-PE to yellow
in BCR-stimulated cells indicated that most of the endocytosed BCR
complexes were contained within the lamp-1+-aggregated
vesicles. However, to exclude the possibility that coregionalization
and not colocalization was occurring, we performed immunoelectron
microscopy. The BCR on A20 cells was labeled by first incubating cells
on ice with rabbit anti-mouse IgG2a, followed by 5-nm gold
particle-conjugated anti-rabbit IgG. The cells were then stimulated
by warming to 37°C for 20 min and fixed, and then frozen sections
were prepared and stained with ID4B (15-nm gold). In stimulated cells,
large lamp-1+ vesicles were found, many in excess of 1 µm
in diameter (Fig. 1B). Many of these vesicles
contained multimembranous intraluminal bodies, reminiscent of those
described in late endosomes (28). Most of the internalized BCR
complexes detected within the lamp-1+ vesicles were within
the intraluminal bodies (left panel). Less
frequently, internalized IgG complexes were found within the vesicle
wall (right panel). Surprisingly, large
lamp-1+ vesicles were absent in unstimulated cells,
suggesting that the BCR was inducing fusion within the
lamp-1+ compartment. To explore this possibility, we used
immunoelectron microscopy to examine the size distribution of
lamp-1+ vesicles in unstimulated and BCR stimulated
cells.
BCR signals vesicular coalescence
We began our analysis by measuring all of the
lamp-1+ membrane-bound structures found in random
fields of electron micrographic images from unstimulated and stimulated
cells. The relative volume of each structure was then estimated from
their average radius. As shown in Figure 2A, only small vesicles with
average volumes of 190 (arbitrary units) were observed in unstimulated
cells (total vesicles counted, n = 50). These vesicles
had an average radius of 40 nm and they lacked the intraluminal
bodies seen within the vesicles of stimulated cells (data not shown).
When we examined stimulated cells, two new populations of larger
vesicles were observed (n = 100). One
intermediate population, which constituted 15% of the total vesicles,
had an average volume of 1120. The second population, which constituted
9% of the total, consisted of very large vesicles with an average
relative volume of 4750. Although only a minority of the vesicles in
stimulated cells were either intermediate or large in size, they
contained >70% of the luminal volume of the lamp-1+
population.
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B, following stimulation the volume of the
lamp-1+ compartment increased by 1.9-fold, while the
surface area between the two groups did not change. It might have been
predicted that the fusion of transport structures bearing endocytosed
BCR complexes with the lamp-1+ compartment would increase
its’ overall surface area. However, most of the endocytosed complexes
were found in intraluminal bodies (Fig. 1B) and
therefore did not contribute to the limiting wall of the vesicles.
We next asked whether the coalescence of lamp-1+ vesicles
occurred in response to biochemical signals generated by the BCR. Since
all known signaling functions of the BCR are dependent on tyrosine
kinase activation (29), we first determined whether the tyrosine kinase
inhibitor genistein would affect coalescence. As seen in Figure 3, preincubation of cells with genistein
inhibited the ability of the BCR to induce the coalescence of
lamp-1+ vesicles. We next assayed for which tyrosine
kinase-dependent pathway(s) might be involved. PI 3-kinase seemed to be
a good candidate because it has been implicated in a myriad of cellular
processes including the fusion of early endosomes (30). However,
pretreatment of cells with the PI 3-kinase inhibitor wortmannin had no
effect on lamp-1+ vesicular coalescence. In contrast,
treatment with PMA and ionomycin, which can recapitulate the signaling
activities of the Ag receptors (31), strongly induced coalescence. PMA
alone induced a partial response, while ionomycin alone did not (data
not shown). These observations suggest that PKC, which is downstream of
both Ras and phospholipase C, may be involved (32). Indeed,
preincubation with the PKC inhibitor staurosporin inhibited
coalescence. These data indicate that the activation of PKC by one or
more pathways may be necessary for vesicular coalescence.
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Our observation that the BCR traffics to and persists within the
coalescence of lamp-1+ vesicles suggests a role for
the vesicular complex in Ag presentation. Therefore, unstimulated and
stimulated cells were stained with Abs to the cytoplasmic tail of the
ß-chain of MHC class II (green) and lamp-1 (red). In unstimulated
cells, there was bright staining for MHC class II molecules on the
plasma membrane, while most of the cytoplasmic MHC class II was found
within a subset of the lamp-1+ vesicles (Fig. 4, top panels). Upon
receptor stimulation, the cytoplasmic MHC class II redistributed to the
same lamp-1+ complex (Fig. 4) targeted by the BCR (data not
shown). This compartment also contains Ii, which is necessary for the
stabilization of newly synthesized MHC class II and its transport to
the peptide loading compartment (Fig. 4, bottom
panels). Interestingly, within the complex there are
distinctly Ii+ (small arrow) and Ii- (large
arrow) subcompartments. Thus, this complex of vesicles contains Ag, MHC
class II, and Ii, giving it the essential characteristics that have
defined other peptide loading compartments. The compartment is derived
from late endosomes and therefore most closely resembles the previously
described MIIC compartment (14, 33).
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, bottom
panels). Upon stimulation, large new acidic structures
formed, which colocalized with internalized receptor (yellow).
Costaining with ID4B and another acidic dye that can stain
permeabilized cells (Lysosensor, Molecular Probes) demonstrated that
the newly acidified structure costained with lamp-1 (data not
shown). In summary, the BCR is capable of generating tyrosine kinase-dependent signals that regulate both the physical and biochemical properties of an MIIC-like compartment. It is easy to understand how decreasing the pH of the processing compartment could facilitate Ag degradation. The benefits associated with the aggregation and fusion of constituent compartment vesicles is less evident. However, fusion within the lamp-1+ aggregate does not simply result in larger homogenous vesicles. Rather, as demonstrated by the heterogeneous distribution of Ii, it establishes different complex microenvironments in proximity to one another. This may allow the different processes involved in the generation of MHC class II/peptide complexes, such as Ii degradation and peptide loading, to occur under conditions that are optimal for each (35).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marcus Clark, University of Chicago, Department of Medicine, MC0930, Chicago, IL 60637. E-mail address:
3 Abbreviations used in this paper: BCR, B cell Ag receptor; PI 3, phosphatidylinositol 3; IMDM, Iscove’s modified Dulbecco’s medium; TfR, transferrin receptor; lamp-1, lysosome-associated membrane protein; PE, phycoerythrin; Ii, invariant chain; PKC, protein kinase C; MCII, MHC class II peptide-loading compartment.
Received for publication March 4, 1998. Accepted for publication March 25, 1998.
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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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M. van Ham, M. van Lith, B. Lillemeier, E. Tjin, U. Gruneberg, D. Rahman, L. Pastoors, K. van Meijgaarden, C. Roucard, J. Trowsdale, et al. Modulation of the Major Histocompatibility Complex Class II-associated Peptide Repertoire by Human Histocompatibility Leukocyte Antigen (HLA)-DO J. Exp. Med., March 27, 2000; 191(7): 1127 - 1136. [Abstract] [Full Text] [PDF]
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H. A. Anderson, D. T. Bergstralh, T. Kawamura, A. Blauvelt, and P. A. Roche Phosphorylation of the Invariant Chain by Protein Kinase C Regulates MHC Class II Trafficking to Antigen-Processing Compartments J. Immunol., November 15, 1999; 163(10): 5435 - 5443. [Abstract] [Full Text] [PDF]
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M. Gromme, F. G. C. M. Uytdehaag, H. Janssen, J. Calafat, R. S. van Binnendijk, M. J. H. Kenter, A. Tulp, D. Verwoerd, and J. Neefjes Recycling MHC class I molecules and endosomal peptide loading PNAS, August 31, 1999; 96(18): 10326 - 10331. [Abstract] [Full Text] [PDF]
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P. C. Cheng, C. R. Steele, L. Gu, W. Song, and S. K. Pierce MHC Class II Antigen Processing in B Cells: Accelerated Intracellular Targeting of Antigens J. Immunol., June 15, 1999; 162(12): 7171 - 7180. [Abstract] [Full Text] [PDF]
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K. Siemasko, B. J. Eisfelder, C. Stebbins, S. Kabak, A. J. Sant, W. Song, and M. R. Clark Ig{alpha} and Ig{beta} Are Required for Efficient Trafficking to Late Endosomes and to Enhance Antigen Presentation J. Immunol., June 1, 1999; 162(11): 6518 - 6525. [Abstract] [Full Text] [PDF]
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F. Luton and K. E. Mostov Transduction of Basolateral-to-Apical Signals across Epithelial Cells: Ligand-stimulated Transcytosis of the Polymeric Immunoglobulin Receptor Requires Two Signals Mol. Biol. Cell, May 1, 1999; 10(5): 1409 - 1427. [Abstract] [Full Text]
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B. K. Brown, C. Li, P. C. Cheng, and W. Song Trafficking of the Igalpha /Igbeta Heterodimer with Membrane Ig and Bound Antigen to the Major Histocompatibility Complex Class II Peptide-loading Compartment J. Biol. Chem., April 16, 1999; 274(16): 11439 - 11446. [Abstract] [Full Text] [PDF]
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F. Forquet, N. Barois, P. Machy, J. Trucy, V. S. Zimmermann, L. Leserman, and J. Davoust Presentation of Antigens Internalized Through the B Cell Receptor Requires Newly Synthesized MHC Class II Molecules J. Immunol., March 15, 1999; 162(6): 3408 - 3416. [Abstract] [Full Text] [PDF]
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V. S. Zimmermann, P. Rovere, J. Trucy, K. Serre, P. Machy, F. Forquet, L. Leserman, and J. Davoust Engagement of B Cell Receptor Regulates the Invariant Chain-Dependent MHC Class II Presentation Pathway J. Immunol., March 1, 1999; 162(5): 2495 - 2502. [Abstract] [Full Text] [PDF]
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K. Serre, P. Machy, J.-C. Grivel, G. Jolly, N. Brun, J. Barbet, and L. Leserman Efficient Presentation of Multivalent Antigens Targeted to Various Cell Surface Molecules of Dendritic Cells and Surface Ig of Antigen-Specific B Cells J. Immunol., December 1, 1998; 161(11): 6059 - 6067. [Abstract] [Full Text] [PDF]
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