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IMMUNOBIOLOGY
From the Department of Immunology and Microbiology, Dartmouth
Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New
Hampshire; the Department of Immunology, University Hospital Utrecht,
Utrecht, The Netherlands; and the Department of Medicine, Rheumatology
Section, Division of Biological Sciences, and The Pritzker School of
Medicine, University of Chicago, Chicago, IL.
The mechanism of enhanced presentation of ovalbumin (OVA)
internalized as immunoglobulin A (IgA)-OVA via the IgA Fc receptor (Fc Immunoglobulin-A (IgA) synthesis exceeds that of
any other isotype and is a prominent feature of immune responses at
mucosal sites.1 Because these sites are under continuous
challenge by environmental antigens and pathogens, IgA-antigen
complexes are being constantly formed and processed for removal. IgA
receptor (Fc Monocytes and macrophages are also capable of presenting antigen to T
cells in context of major histocompatability complex (MHC) class
II.4 While these cells can take up antigen
non-specifically, antigen presentation is dramatically increased when
antigen is complexed with antibody. Manca et al5
demonstrated that polyclonal antibody enhanced macrophage presentation
of beta galactosidase by more than 100-fold and that Fc It is not known whether the FcR plays an active role in enhanced
processing, based on its ability to signal, or whether it merely allows
capture of greater amounts of antigen. Several of the FcRs, including
Fc Fc For the altered B-cell transfectant and T-cell culture
Antigen presentation with B-cell transfectants For studies on Fc R-mediated antigen uptake, OVA (Worthington
Biochemical, Lakewood, NJ) was derivatized with NIP (nitro-iodophenol caproate-o-succinimide) (Genosys, The Woodland, TX) to give an average
of 3 NIP haptens per OVA. For derivatization, NIP was dissolved in
dimethyl formamide and added to OVA dissolved in borate-buffered saline
(pH 8.3). After 1.5 hours, the mixture was dialyzed into
phosphate-buffered saline (PBS) (pH 7.4). Soluble IgA-OVA complexes
were made by mixing chimeric human IgA2 anti-NIP (gift from Drs
R. Jefferis and D. M. Goodall, University of Birmingham, Edgebaston, England) with NIP-derivatized OVA at a molar ratio of 3:1.
Studies on nontargeted antigen uptake used nonderivatized OVA. We
cultured IIA1.6 cells in duplicate with IgA anti-NIP/NIP-OVA complexes
(IgA-OVA) or OVA alone and OVA-specific DO-11-10 T cells at a 4:1 ratio
for 20 hours, after which supernates were removed and frozen. Antigen
presentation was measured by assaying the ability of serial dilutions
of supernate to promote survival of the IL-2-dependent T cell line
HT-2. The results are expressed as mean and spread of duplicates in
representative experiments. In this well-documented assay system,
titers that differ by 4-fold or more are considered significantly
different.12
Flow cytometry of cell surface markers The levels of MHC class II, Fc R, and costimulatory molecules
on the IIA1.6 transfectants were measured by direct or indirect immunofluorescence staining and flow cytometry in comparison to isotype-matched negative control antibodies. Fc R was
detected using My43, a Fc R-specific IgM mAb produced in our
laboratory,13 and fluorescein isothiocyanate (FITC)
anti-mIgM (Caltag Laboratories, South San Francisco, CA).
I-Ad was detected using FITC-labeled M5 (gift from Dr R. Noelle, Dartmouth Medical School, Lebanon, NH). Costimulatory molecules
were measured with commercially prepared antibodies (PharMingen, San
Diego, CA): ICAM-1 using phycoerythrin (PE)-labeled 3E2, B7-1 using
PE-labeled 16-10A1, and B7-2 using FITC-labeled GL-1.
RNA isolation and reverse transcriptase-polymerase chain reaction Total cellular RNA was isolated from sheared cells using Trizol (Gibco), and 2 µg RNA from each preparation was transcribed into DNA. We performed -chain polymerase chain reaction (PCR) using 2 -chain-specific primers encompassing the transmembrane region of
chain. The sequence of the 5' oligomer primer was 5'-CAG CCG TGA
TCT TGT TC-3', and the sequence of the 3' oligomer primer was 5'-CTC
ACG GCT GGC TAT AGC-3'. After a 2-minute denaturing step the PCR was
performed for 25 cycles (94°C, 52°C, and 70°C for 15 seconds
each) with a 5-minute final extension at 70°C. Aliquots of 10 µL
from each reaction were analyzed by agarose gel electrophoresis.
Endocytosis Transfectants were incubated with a naturally polymeric human IgA myeloma protein for 1.5 hours on ice. The cells were then washed, and one aliquot was kept on ice. The remaining cells were incubated at 37°C in culture medium and transferred into ice-cold medium at the indicated times. All cells were subsequently stained with FITC antihuman IgA (Jackson Immunoresearch Laboratories, West Grove, PA). Negative control cells were identically treated but did not receive IgA. The amount of surface-bound IgA was measured by flow cytometry.Catabolism studies For studies of IgA catabolism by Western blot analysis, transfected B cells were incubated with polymeric human IgA myeloma protein at the concentrations stated. At the indicated times, cells were pelleted, subjected to 2 PBS washes, and lysed in 1% NP-40 containing a protease inhibitor cocktail (Boehringer Mannheim, Indianapolis, IN). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot using HRP antihuman IgA (Jackson Immunoresearch) and enhanced chemiluminescence (ECL) (Amersham Life Sciences, Arlington, IL) were used to detect IgA digestion products.Catabolism of iodine 125 (125I) antimouse IgM µ chain
(ICN Pharmaceuticals, Irvine, CA) was examined by first coating
2 × 106 transfected B cells on ice with the IgM
anti-Fc Tyrosine phosphorylation Tyrosine phosphorylation was assessed after cross-linking Fc R
on the transfectants with My43 for 15 minutes. Following one wash,
anti-mIgM (Jackson Immunoresearch) was added. After 2 minutes at 37°C
the cells were transferred into ice-cold lysis buffer containing 4 mM
Na3 VO4 (sodium vanadate), 20 mM NaF (sodium
fluoride), and 1% NP-40. Whole-cell lysates were analyzed by SDS-PAGE
and transferred to nitrocellulose membranes. Equal loading and transfer of the samples to the membranes were ascertained by ponceau red staining. Membranes were stained for 5 minutes in 0.5% ponceau red/1%
acetic acid followed by distilled water rinsing to remove unbound
stain. The membranes were destained with 3 PBS washes of 5 minutes each. Tyrosine-phosphorylated proteins were then detected by
Western blot using HRP-labeled antiphosphotyrosine (Upstate
Biotechnology, Waltham, MA) and ECL.
Confocal microscopy For Fc R/lamp-1 costaining, cells were first incubated with
A77, an IgG1 anti-Fc R mouse mAb. This was followed by FITC antimouse IgG1 (Jackson Immunoresearch) for 10 minutes at 4°C, then washing. The cells were then warmed to 37°C and incubated for 30 minutes, fixed with 3% paraformaldehyde/3% sucrose, and permeabilized with 0.05% saponin as described.14 Cells were then incubated
for one hour at ambient temperature with the anti-lamp-1 mAb ID4B (gift from Andrea Sant, University of Chicago, Chicago, IL), washed, and stained with anti-rat IgG Cy3 (Jackson Immunoresearch). Confocal sections of approximately 0.75-1 µm were acquired using a Zeiss 410 confocal microscope and displayed by pseudo-coloring using LSM software
(both from Zeiss, Oberkochen, Germany.)
Targeted and nontargeted antigen presentation While monocytes express Fc R and are capable of antigen
presentation, the endogenous expression of chain by monocytes
precludes a detailed investigation of the role of chain in
Fc R-enhanced antigen presentation. Whether Fc R makes an active
contribution to antigen processing or serves only to capture IgA-coated
antigen at the APC surface is the focus of the present study in which we examined the role of the Fc R-associated chain and in
particular the -chain ITAM. This motif is required for receptor
signaling, however tyrosine motifs also play a role in FcR endocytosis,
a necessary first step in antigen processing.15 To study
the -chain ITAM, IIA1.6 B cells were stably cotransfected with
Fc R plus WT or altered chain and compared for ability to present
IgA-OVA to DO-11-10 T cells. The results in Figure
1A show that the Fc R + WT transfectant presented IgA-OVA more effectively than either the
transfectant with the IIA ITAM mutant chain or the Y F chain, in that 10-fold less IgA-ag was required by the Fc R + WT
transfectant to achieve 40 units of IL-2 production. In the absence
of antigen, IL-2 production was undetectable. In addition, nontransfected IIA1.6 cells were completely lacking in ability to
present IgA-OVA at these concentrations (data not shown.)
To determine that the transfectants with altered The transfectants expressed similar levels of Fc
Endocytosis and catabolism of IgA aggregates The ITAM of the chain is known to be required for
phagocytosis,17 thus it was possible that differences in
internalization of the IgA-OVA complexes accounted for the disparate
levels of IgA-OVA presentation. We therefore examined the ability of
the transfectants to endocytose polymeric IgA. Cells were coated with IgA, washed, and incubated at 4°C or 37°C for 1 hour, after which they were stained with FITC anti-IgA to measure surface-bound IgA.
Figure 3 shows that incubation at 37°C
reduced surface IgA by 63% in Fc R/WT chain, 64% in Fc R/IIA
ITAM chain, and 66% in Fc R/Y F chain compared to cells
held at 4°C in otherwise identical conditions. The results,
representative of 3 individual experiments, demonstrate that the
transfectants had equal capacity for Fc R-mediated endocytosis.
Thus, IgA complexes appeared to enter the endocytic pathway equally in
the transfectants, raising the possibility that postendocytic processing differences might account for the disparity in presentation of IgA-OVA. Therefore, we examined the catabolism of 2 Fc
While measurement of release of TCA-soluble radio-label is a good
measure of overall ligand degradation, it gives no information on the
processing of peptides derived from the ligand. We reasoned that
analysis of catabolism by Western blotting, which detects epitopes
formed by the protein structure, might be a useful adjunct to
measurement of TCA-soluble counts for catabolism studies. Figure 4B
shows the results of an experiment (representative of 3) in which the
cells were allowed to ingest polymeric IgA for 4 hours at 37°C, after
which they were lysed and analyzed by SDS-PAGE and Western blot with
HRP anti-IgA. In Figure 4B the Fc We also compared the ability of the different transfectants to
catabolize the BCR ligand, goat anti-mIgG. The transfectants showed
equal degradation of this ligand (data not shown.) Thus, by 2 different
assay methods, the impaired ability to catabolize Fc Intracellular localization of Fc R/ -chain transfectants to determine whether
Fc R ligation and its attendant -chain signaling produced a
similar morphological change and transport of ligated Fc R to
lamp-1+ vesicle clusters. We also addressed whether Fc R
with altered chain was capable of inducing MIIC formation.
Figure 5 shows the intracellular location
of anti-Fc
Signaling in response to Fc -chain homodimer associates with FcR, such as Fc RI,
Fc RIIIA, and Fc R, which lack signaling motifs in their
cytoplasmic domain. The cytoplasmic domain of chain contains an
ITAM, enabling these FcRs to transduce signals.17,19 Our
data demonstrate that Fc R cotransfection with chains containing
altered ITAM regions produces diminished ability to catabolize IgA and
to present IgA-OVA. This led us to investigate whether Fc R signaling
was also defective in these cells. Following Fc R ligation for 2 minutes, tyrosine-phosphorylated proteins were observed at
approximately 100, 80, and 70 kd in lysates of the transfectant with WT
chain (Figure 6A). Similar
phosphorylated proteins of lower intensity were obtained after Fc R
ligation of the transfectant with IIA ITAM chain. These bands were
almost undetectable in lysates of the transfectant with Y F chain. The same nitrocellulose membrane was stained with ponceau red, a
sensitive protein stain (Figure 6B). This staining demonstrated that
phosphorylation differences could not be attributed to unequal amounts
of lysate between lanes. The heavy band at approximately 70 kd in lane
3 of the WT, IIA ITAM, and Y F samples was µ chain-derived from
the anti-Fc R mAb My43 used for activation. These results were
reproduced in 3 independent experiments. Longer incubations before
lysis did not result in appearance of phosphorylated proteins in the
transfectants with altered chain (data not shown.) In contrast to
Fc R, the amount of phosphorylation in response to BCR cross-linking
was the same in all transfectants (data not shown.) These results indicated that the transfectants with altered chains, which were
less capable of IgA catabolism, Fc R/lamp-1 colocalization, and
IgA-OVA presentation, were also deficient in Fc R-mediated signaling.
Augmentation of IgA-OVA presentation and IgA catabolism by BCR cross-linking A previous study by Casten and Pierce20 demonstrated that B-cell presentation of nonspecifically internalized antigen was augmented by ligating the BCR with anti-Ig. These findings suggested that signaling could augment the processing of an antigen that was not physically associated with the signaling receptor. We were interested in the possibility that BCR signaling might augment the defective presentation of IgA-OVA associated with Fc R/IIA ITAM and Fc R/Y
F -chain receptor complexes. Our rationale was that if signaling
were to play a role in driving antigen processing, then BCR signaling
might compensate for the defective signaling of Fc R in these
transfectants. Indeed, we observed that presentation of Fc R-targeted
OVA was enhanced in the IIA ITAM and Y F -chain transfectants by
treating the transfected cells with antimouse IgG at a concentration
(10 µg/mL) that promoted BCR signaling (Figure
7A,B).
We also examined the effect of BCR ligation on the ability of the
Fc Augmentation of nontargeted OVA presentation by BCR
and Fc R, might increase presentation of OVA
taken up nonspecifically. To test this idea we compared the
signaling-competent BCR and Fc R/WT chain with
signaling-defective Fc R/IIA ITAM and Fc R/Y F -chain
transfectants for ability to augment the presentation of low levels of
nontargeted OVA. At concentrations of OVA that gave suboptimal levels
of antigen presentation, cross-linking of BCR with anti-IgG enhanced
presentation in all transfectants irrespective of whether they had WT
or altered chain (Figure 8A-C). In
contrast, when Fc R was cross-linked with My43 (mIgM) and anti-IgM,
presentation of suboptimal amounts of OVA was enhanced only in the
transfectant with WT chain (Figure 8D). Fc R cross-linking did
not enhance OVA presentation in transfectants with IIA ITAM or Y F
chain (Figure 8E,F, respectively). It should be noted that IIA1.6
cells do not express surface IgM. These results were reproduced in 3 independent experiments.
It has been reported that IIA1.6 cells are capable of secreting IL-2 in
response to certain receptor cross-linking treatments.12 We did not observe IL-2 secretion by any of our transfectants in
response to either BCR or Fc
It is known that Fc receptors mediate the enhanced presentation of
IgG-complexed antigen; however, the intracellular mechanisms leading to
the enhancement of presentation are not fully understood.21 Two cellular processes involved in presentation are the targeting of
antigen to processing compartments by FcR motifs and the intracellular trafficking of antigen. We hypothesize that Fc Fc Cells transfected with Fc We observed a correlation between the ability of Fc We observed inability of altered Confocal microscopy showed differences in the distribution of
internalized Fc A role of signaling in receptor-enhanced antigen presentation was
further suggested by our observation that signals associated with
enhanced antigen presentation can be provided in trans to the receptor
that internalizes the antigen. BCR cross-linking elevated the
presentation of IgA-OVA by transfectants with altered In summary, we propose that the Fc
Supported by grants AI 22816, GM52736, and AI35306 from the National Institutes of Health, Bethesda, MD, and by grant 901-12-214 from NWO (Netherlands Organization for Scientific Research), Den Haag, The Netherlands.
Submitted April 4, 2000; accepted August 25, 2000.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Li Shen, Department of Microbiology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH 03756; e-mail: lilian.shen{at}dartmouth.edu.
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© 2001 by The American Society of Hematology.
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