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*
Centre d’Immunologie, Centre National de la Recherche Scientifique-Institut National de la Santé et de la Recherche Médicale de Marseille-Luminy, Marseille, France; and
Laboratory of Tumor Immunology, Scientific Institute Hospital San Raffaele, Milan, Italy
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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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- and ß-chains of MHC class II heterodimers associate
with the invariant chain
(Ii)3 in the endoplasmic
reticulum and are transported to endocytic compartment(s) where they
meet antigenic peptides derived from exogenous proteins 1, 2, 3, 4, 5, 6 . The
peptide loading process is facilitated by the presence of H2-M
molecules involved in the dissociation of Ii fragments from the class
II peptide binding groove 7, 8, 9 . The intracellular route(s) followed
by class II-Ii complexes from the trans-Golgi network to the endocytic
pathway remain(s) incompletely characterized, although direct targeting
to early endosomes, and indirect recycling via the plasma membrane,
have been proposed 2, 6, 10, 11, 12, 13, 14 . A di-leucine targeting motif present
in the cytoplasmic tail of Ii plays a pivotal role in the control of
the movements of class II-Ii complexes through the endocytic pathway
(reviewed in 15 . Ii is a major regulator of the trafficking of
newly synthesized class II molecules among different intracellular
compartments. Ii expression influences class II association with
peptides derived from protein cores 16 . In B cells, newly synthesized
class II molecules are targeted by Ii to intracellular loading
compartments (reviewed in Refs. 15 and 17). In addition to newly synthesized class II molecules, an alternative Ii-independent pathway of Ag presentation relying on recycled MHC class II molecules has been demonstrated 13, 14 . Class II molecules expressed at the cell surface require a di-leucine motif present in the tail of the class II ß-chain for entry into early endosomes 16 . Cytoplasmic domain truncation mutants of MHC class II molecules fail to present a set of protein determinants and to be internalized in endosomes 13, 14 . The antigenic determinants accessible to this second presentation pathway are thought to be produced in early endosomal compartments from endocytosed protein under conditions of mild proteolytic degradation and can be loaded onto recycled MHC class II molecules 13, 14, 16 . This recycling pathway does not require either protein synthesis or the presence of Ii 18 .
B cells generated from mice bearing a genetically disrupted Ii gene
show a striking alteration in the intracellular transport and
maturation of class II molecules 19, 20, 21 . Ii requirement for class II
dimerization differs between haplotypes 22 . In the H-2k
haplotype, - and ß-chains efficiently assemble in the absence of
Ii 22 . However, in these mice, Ii-deficient B cells were able to
present to T cells only peptides generated in early endocytic
compartments that associate with recycled MHC class II molecules after
Ag uptake by fluid phase endocytosis 19, 23 . The stringency of Ii
requirement for MHC class II peptide loading differs also in different
cell types. We showed recently that Ii-deficient dendritic cells (DC)
from H-2k mice present a broad range of peptides generated
from hen egg lysozyme (HEL), regardless of their position in the
protein sequence 23 . The heterogeneity observed for class II assembly
and transport in different cell types may reflect physiologically
important functional or developmental differences between them 23, 24 .
B cells use the B cell receptor (BCR) to mediate efficient uptake and
concentration of exogenous Ags. The BCR is a complex comprising
membrane Ig molecules sheathed by noncovalently associated Ig and
Igß molecules, which are responsible for Ag endocytosis and
transmembrane signaling 25, 26 . In B lymphoma cells, engagement of
the BCR initiates a cascade of signaling events 26 that induce
intracellular accumulation of MHC class II-Ii complexes 27, 28 and
up-regulates costimulatory molecules. These events contribute to the
ability of B cells to present their cognate Ags at extremely low
concentrations 29, 30, 31, 32, 33 . Most attempts to address the role of Ii in Ag
presentation have relied on cells that were allowed to internalize Ag
by fluid phase endocytosis. However, B cells are unlikely to present
such nonspecifically internalized Ag in a physiological context.
To address the role of Ii in presentation of Ag internalized through the BCR, we crossed transgenic mice expressing an HEL-specific Ig molecule in their BCR complex with mice in which the Ii chain had been genetically deleted. We evaluated by confocal microscopy the relationship between BCR engagement and Ag compartmentalization. We also evaluated effects on Ag recognition by T cells. We wished in particular to determine the effect of BCR targeting on the presentation of three HEL-derived peptides that are classically defined as "Ii-dependent" or "Ii-independent" 18 . As expected, BCR targeting was found to increase the efficiency of all HEL-derived peptides by orders of magnitude. However, we found that BCR ligands are uniquely presented by the Ii-dependent Ag presentation pathway regardless of the peptide analyzed. This is consistent with our observation that BCR ligands are delivered into compartments in which the accumulation of MHC class II molecules is induced or markedly increased by engagement of the BCR.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B10BR mice (H-2k) bearing a genetically disrupted Ii gene (Ii-/-) were generously provided by D. Mathis and C. Benoîst (Strasbourg, France) 19 . The absence of Ii was tested by both Southern and Western blot analysis as described 23 . CBA/J mice (H-2k) bearing a transgenic BCR (IgM and IgD) (Tg BCR+/-) specific for HEL were previously described 34, 35 . The F1 generation between Ii-/- mice and Tg BCR+/- mice, Tg BCR+/-/Ii+/-, was back-crossed with the Ii-/- mice. F2 Tg BCR-/Ii+, Tg BCR+/Ii+, Tg BCR-/Ii-, and Tg BCR+/Ii- littermates were used in all experiments. Mice were routinely characterized for Ii and Tg expression by Southern and Western blot and PCR (see below).
Southern blots, Western blots, and PCR.
To monitor Ii gene disruption, 21-day-old mice were routinely tested by Southern blot as described 19 . Ii protein expression was also monitored by Western blot using an anti-Ii cytoplasmic domain Ab 23, 27 . The expression of the BCR specific for HEL protein was monitored by PCR. Tail DNA aliquots (2 µg) were amplified using two specific primers (final concentration, 2 pM) (5'-GCG ACT CCA TCA CCA GCG AT-3' and 5'-ACC ACA GAC CAG CAG GCA GA-3') in the following conditions: 5 min of denaturation (94°C), 30 cycles of amplification (30 s at 94°C, 30 s at 64°C, and 30 s at 72°C) and a cycle of elongation (5 min at 72°C). The products of PCR were analyzed on a 2% agarose gel. The presence of the transgene resulted in the amplification of a single fragment of 430 bp.
Media and cells
RPMI 1640 or DMEM medium (Sigma, St. Louis, MO) were supplemented with 5 mM L-glutamine, 100 IU/ml penicillin, 100 µg/ml streptomycin (all from Life Technologies, Paisley, Scotland), 50 µM ß-mercaptoethanol, and 10% heat-inactivated FCS (BioMedia, Walkersville, MD). The isolation of B splenocytes was essentially performed as reported 23 . T lymphocytes were depleted from spleen cells by Ab- and complement-mediated lysis (anti-Thy1, anti-CD4, anti-CD8). B cell enrichment varied between 85–95%, depending on the preparation as detected using the anti-CD45R mAb. The I-Ak-restricted T cell hybridomas (3A9, 3B11, and 2B6) were generously provided by L. Adorini (Milan, Italy) and cultured as described 18, 23, 36, 37 . The I-Ak-restricted 3A9, 3B11, and 2B6 T cells are specific for the 46–61, 34–45, and 25–43 HEL peptides, respectively 18, 36 . IL-2-dependent CTLL-2 cells (American Type Culture Collection (ATCC), Manassas, VA) were cultured in complete DMEM supplemented with 10 U/ml IL-2.
Antibodies
Hybridomas producing anti-mouse MHC class
II-I-Ak molecule (10.2.16), anti-mouse Fc
II/III
receptor (2.4G2), anti-mouse ICAM-1, anti-mouse Thy1 (J1J),
anti-mouse CD4 (RL172Y), and anti-mouse CD8 (31 M) were all
from ATCC. The 10.2.16 Ab precipitates compact and noncompact class II
dimers. The hybridoma producing anti-mouse HEL peptide
46–61/I-Ak complex (C4H3) was kindly provided by R.
Germain (National Institutes of Health, Bethesda, MD) 38 . The rabbit
polyclonal Abs against the cytoplasmic domain of Ii, I-A
ß-chains and H2-M ß-chains, were a gift of N. Barois
(Marseille, France) 27 . Anti-CD45R, anti-B7.1, anti-B7.2, and
anti-CD40 mAbs were all from PharMingen (San Diego, CA). The second
step reagents and the anti-mouse IgM, IgD, and IgG were from
Jackson Immunoresearch Laboratories (West Grove, PA). The
anti-idiotypic mAb against the anti-HEL Tg BCR was
previously described 35 .
Surface iodination, immunoprecipitation and SDS-PAGE
B cells (107), incubated 16 h or not with 1 µM HEL protein to induce class II peptide loading in Tg and non-Tg B cells, were labeled by lactoperoxidase-catalyzed iodination as described 19, 23 . After extensive washing, cells were lysed in 0.5% Triton X-100. Class II molecules were immunoprecipitated with the 10.2.16 mAb. Before electrophoresis on an SDS-polyacrylamide gel (12.5%), the samples were either fully denatured at 95°C for 5 min or incubated for 30 min at room temperature in SDS sample buffer containing 5% 2-ME, to preserve the peptide-loaded compact forms of class II heterodimers 39 .
Ag presentation
Ag presentation was performed by incubating, in 96-well flat-bottom plates, 7 x 104 3A9, 3B11, or 2B6 T hybridoma cells with 4 x 104 B cells, in the presence or in the absence of 10-fold serial dilution of the HEL protein or HEL peptide (46–61 peptide) 23 . After 24 h, IL-2 secretion was assessed using thiazolyl blue (MTT) (Sigma) to evaluate the growth of the IL-2-dependent CTLL-2 line.
Immunofluorescence labeling
Cells were stained as previously described 40 . The samples were analyzed using a FACScan instrument (Becton Dickinson, San Jose, CA). To monitor membrane Ig internalization after engagement in Tg BCR+/Ii+ and Tg BCR+/Ii- B cells, cells were incubated either with 10 µM HEL protein for 4 h or 16 h at 37°C or with an anti-mouse IgM Ab (10 µg/ml) for 15 min at 4°C. After extensive washing, cells were either immediately processed for confocal analysis or incubated at 37°C for 1 h. To perform confocal microscopy analysis, cells were first attached to glass coverslips coated with poly-L-lysine (Sigma; 100 µg/ml in distilled water for 1 h at room temperature) in medium devoid of FCS for 20 min at 4°C. Intracellular immunofluorescence was performed as previously described 41 . The confocal laser scanning microscopy was conducted using a Leica TCS 4D instrument (Leica, Heidelberg, Germany) 23, 27 .
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To define the role of Ii during the presentation of BCR-targeted
Ags, we derived B cells from the spleens of Ii-positive and Ii-negative
H-2k B10BR x CBA/J mice expressing or not a Tg BCR
specific for HEL 34, 35 . Regardless of Ii and Tg BCR expression,
splenic B cells expressed high levels of membrane CD45R molecule (Fig. 1
), and virtually all Tg B cells
expressed high levels of the HEL-specific BCR (Fig. 1). The absence of
Ii also did not compromise membrane expression of Igs IgM or IgD, or
adhesion and costimulatory molecules (ICAM-1, B7.1, B7.2, and CD40). In
contrast to cells derived from the H-2b haplotype animals
42 , H-2k Ii-/- B cells efficiently reached
the mature stage, as revealed by the membrane coexpression of IgM and
IgD (Fig. 1). MHC class II surface expression was as expected reduced
in Ii-/- mice independent of Tg BCR expression (Fig. 1).
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). To reveal
peptide-stabilized "compact" membrane-dimers, the SDS extracts were
run after boiling or not. Regardless of BCR expression, MHC class II
molecules were unable to reach the B cell plasma membrane in a stable
"compact" conformation in the absence of Ii (Fig. 2A).
Furthermore, although B cell incubation for 16 h in the presence
of HEL slightly increased the level of stable MHC class II dimers in
Ii-positive B cells, this treatment did not induce compact class II
molecules at the surface of Ii-negative cells, even when they expressed
the HEL-specific BCR (Fig. 2B).
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To analyze the Ii dependence of class II-restricted presentation of HEL taken up by fluid phase or with the BCR, we used a panel of T cell hybridomas. The I-Ak-restricted 3A9 T cell hybridoma is specific for the 46–61 HEL peptide 36 , which mainly associates with newly synthesized I-Ak molecules. 3B11 and 2B6 T cell hybridomas recognize respectively the 34–45 and 25–43 HEL peptides that bind to recycling class II molecules independently of Ii 18 .
Tg BCR-/Ii+ splenic B cells presented HEL
protein at µM concentrations, consistent with fluid phase uptake, to
the 3A9, 3B11, and 2B6 T cell hybridomas (Fig. 3A, open squares). The absence
of Ii compromised the presentation of the 46–61 HEL-derived peptide to
the 3A9 Ii-dependent T cell hybridoma but not the presentation of the
HEL-derived 34–45 and 25–43 peptides to the 3B11 and the 2B6 T cells
in Tg BCR-/Ii- B cells (Ref. 19; and Fig. 3A, filled squares). This is consistent with the proposition
that 3A9 T cell activation requires an intact Ii to target nascent
class II molecules to MHC class II intracellular loading compartments,
while 3B11 and 2B6 T cell activation can be elicited by recycled class
II molecules in the absence of Ii 18 .
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A, open triangles). Surprisingly, Ii-deficient B cells
expressing an HEL-specific BCR failed to efficiently present either the
Ii-dependent 46–61 HEL determinants or the Ii-independent 34–45 and
25–43 HEL determinants (Fig. 3A, filled triangles). The
efficiency of presentation of the 46–61 HEL synthetic peptide was
similar in all B cell types considered (Fig. 3B), even
though the number of MHC molecules was reduced on Ii-deficient cells
(Figs. 1 and 2) and was not increased by incubation with HEL protein
(Fig. 2B). MHC class II molecules require Ii to meet internalized BCRs
The engagement of the BCR leads to a redistribution of newly
synthesized MHC class II molecules 27, 28 . We used confocal
microscopy to determine whether the absence of Ag presentation in
Ii-deficient Tg B cells was associated with an Ii-dependent regulation
of class II transport in response to BCR ligation. Fig. 4 shows the distribution of the
HEL-specific BCR, H2-M, and class II molecules in B cells before and
after membrane Ig (mIg) engagement. In the absence of BCR engagement in
Ii-positive cells, mIgs and MHC class II molecules were mainly located
at the plasma membrane (Fig. 4a), while H2-M molecules were
localized in internal vesicles (data not shown). Ig engagement resulted
in a dramatic modification of the MHC class II intracellular
distribution (Fig. 4b). mIg engagement by an anti-IgM Ab
induced their time-dependent transport to intracytoplasmic vesicles.
These sites correspond to the class II peptide loading compartments
since they are partially positive for class II and H2-M molecules (Fig. 4, b and c, respectively).
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, and Fig. 4, a and d).
Some MHC class II molecules reached the plasma membrane while others
were retained as immature glycoproteins in the endoplasmic reticulum
(Ref. 21 and Fig. 4d). The confocal micrographs demonstrate
that BCR engagement does not result in MHC class II colocalization with
the BCR in intracellular compartments in the absence of Ii (Fig. 4e), despite the fact that BCR ligands colocalize with H-2 M
molecules in internal vesicles in Ii-negative cells to the same extent
that they did in Ii-positive cells (Fig. 4, c and
f).
We also evaluated Tg B cells incubated or not with their cognate
ligand, HEL. Resting HEL-specific B cells displayed little or no
intracellular class II molecules (Fig. 5a), and this pattern did not
change after overnight incubation in medium alone (not shown). After
16 h of HEL incubation followed by fixation, internal class II
molecules were detectable and mainly colocalized with internalized BCR
(arrows in Fig. 5, c and b, respectively). As in
the case when we incubated cells with an anti-IgM Ab (Fig. 4), no
colocalization of class II with the BCR was seen in Tg B cells lacking
Ii when incubated with HEL (data not shown). To assess whether
intracellular class II molecules were loaded with the 46–61 peptide,
we used the C4H3 mAb, which recognizes HEL 46–61 in the context of
I-Ak molecules. After 4 h or 16 h of HEL
incubation, the internalized BCR partially colocalized with 46–61
peptide-loaded I-Ak molecules (arrows, Fig. 5, d
and e, respectively). Faint background staining with the
C4H3 Ab in cells incubated without HEL, apparently due to
cross-reactive self peptides, has been reported 38 but was not seen
by us in confocal microscopy in the absence of HEL (data not shown).
This background staining was observed in FACS studies, but the binding
of the C4H3 Ab was markedly increased by incubation with HEL (Fig. 5f). Thus, BCR engagement of cognate ligands induces the
accumulation of class II molecules at sites where they are available
for peptide loading in Ii-positive spleen cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There may be several explanations for this result. 1) The physical association between the Ag and this high affinity 47, 48 BCR involved in endocytosis delivers the Ag into a class II recycling compartment but interferes with the initial phases of the degradation process, as already discussed 49, 50, 51 . This would prevent the generation and association of peptides in early endosomal compartments with recycling MHC class II molecules. Ags bound to the BCR are also internalized more rapidly than Ags bound to other cell-surface molecules, which could limit their exposure to the proteolytic environment of early endosomes 52 . In this situation, only newly synthesized MHC class II molecules transported by Ii would have the opportunity to interact with peptides generated in deeper endocytic compartments. 2) Ags internalized through the BCR could follow a route of internalization that bypasses early intracellular compartments where class II recycling occurs. Our results do not exclude either of these possibilities. The observation that BCR engagement by anti-Ig or specific Ag initiated an accumulation of MHC class II molecules in peptide loading compartments in a manner dependent on the expression of Ii provides a basis for augmented Ag presentation to T cells. These results confirm and extend to normal B cells our observations 27 , as well as recent results of Siemasko et al. 28 , that internalized Ig accumulates in compartments rich in newly synthesized class II molecules. We also show that this compartmentalization correlates with efficient Ag presentation to naive T cells.
It has been known for a long time that the quantitative advantage for
Ag acquisition for BCR-mediated Ag uptake cannot account for all of the
gain in Ag presentation, since Ag targeted to molecules expressed at
comparable levels were nonetheless much less well presented 53, 54 .
Despite equivalent internalization, as compared with membrane Ig
containing heterologous cytoplasmic motifs from other expressed
proteins such as LDL and MHC class I, BCR-mediated Ag uptake was shown
to lead to an accelerated intracellular targeting and presentation in B
cell transfectants 52 . Evidence has been presented indicating that
mutating a single amino acid in the transmembrane region of human IgM
may inhibit the ability of cells expressing this molecule to present
Ag, while leaving bulk Ag endocytosis and degradation intact 31 . In
addition, experiments using cells transfected with Fc receptor Ig or
Igß chimeras have shown that the Ig-chain directs Ag to a
compartment containing newly synthesized class II molecules, while
Igß targets Ag to a population of recycling class II-containing
vesicles 55 .
B cells appear to have other means to differentially control BCR-mediated Ag presentation in a manner involving class II molecules. The H2-O molecule, which regulates the catalytic function of H2-M in releasing class II-associated invariant chain-derived peptides (CLIP) from class II molecules 56, 57 , was shown to focus B cell presentation on Ags internalized by the BCR 58 . Taken together, these data suggest that Ag internalization by the BCR is a tightly regulated process intimately associated with class II maturation. In contrast to B cells, DC capture and present Ags using a broader receptor repertoire 44 . The fact that H2-O molecules are expressed in B cells but not in DC and the differential Ii requirement observed for Ag presentation by dendritic 23 and B cells reinforce the distinction between the strategies used by B cells and DC to load their class II molecules. B lymphocytes rely on newly synthesized molecules "escorted" by Ii, whereas, in DC, Ii is not required for I-Ak peptide presentation 23 . The data presented here, in which we crossed the same Ii-negative H-2k mice with BCR Tg mice, suggest that the expression of Ii is required both for the advantage in Ag presentation conferred by the presence of the Ag-specific BCR and also to promote the intracellular accumulation of MHC class II molecules in response to BCR ligation. The accumulation of class II molecules in compartments accessible to Ag endocytosed by the BCR could account for much of the gain in efficiency of the presentation to T cells of Ii-positive B cells specific Ags.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Lee Leserman, Centre d’Immunologie INSERM-CNRS de Marseille-Luminy, Parc Scientifique et Technologique de Luminy, Case 906, 13288 Marseille Cedex 9, France. E-mail address:
3 Abbreviations used in this paper: Ii, invariant chain; HEL, hen egg lysozyme; DC, dendritic cell; BCR, B cell receptor; Tg, transgenic; mIg, membrane Ig.
Received for publication August 17, 1998. Accepted for publication November 11, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß dimers and facilitates peptide loading. Cell 82:155.[Medline]
and Igß subunits in MHC class II-restricted antigen presentation. Immunity 3:335.[Medline]
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