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The Journal of Immunology, 2001, 167: 632-635.
Copyright © 2001 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Editing of Recycling Class II:Peptide Complexes by HLA-DM1

Sulabha S. Pathak, John D. Lich and Janice S. Blum2

Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
HLA-DM catalyzes the exchange and selection of ligands for MHC class II molecules within mature endosomal/lysosomal compartments. Here, evidence is provided that DM edits peptides in early endosomes, thus influencing presentation via recycling class II molecules. Maximal class II-restricted presentation of an albumin-derived peptide, dependent on endocytosis and recycling class II molecules, was observed in cells lacking HLA-DM. DM editing of this epitope was observed in early endocytic compartments as shown using inhibitors of early to late endosomal transport. Editing was tempered by coexpression of HLA-DO, suggesting that DM:DO ratio may be important in guiding epitope editing in early endosomal compartments. Thus, HLA-DM appears to interact with, and edit epitopes displayed by, recycling class II molecules.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
The MHC class II molecules present peptides derived from exogenous and endogenous proteins to CD4+ T lymphocytes (1, 2, 3). Class II molecules are synthesized in the endoplasmic reticulum and transit through early and late endosomal compartments where peptide loading can occur. The nonpolymorphic MHC-encoded molecule, HLA-DM, facilitates this loading process by acting as a peptide editor with the caveat that another MHC-encoded molecule, HLA-DO, may regulate DM function in select cells (4, 5).

HLA-DM is preferentially localized within mature endosomal/prelysosomal compartments. However, low levels of DM are found in early endosomal compartments of B cells and on the surface of dendritic cells (3, 6, 7, 8, 9, 10). The functional role of DM in these compartments remains unclear. Editing of select peptide:class II complexes at the cell surface was linked to DM expression (10). Yet, DM-independent Ag presentation can occur in early endosomes (11, 12). Although HLA-DM is known to display maximal editing activity at pH 5.5, it retains function at neutral to slightly acidic pH values found in the early endocytic compartments (13). HLA-DO may also play a role in regulating DM function in these locations, because DO limits peptide editing by DM at neutral, but not acidic, pH (4, 5). Here, evidence is provided that HLA-DM can act as an editor in early endosomes and influence the presentation of peptides via recycling class II molecules. Thus, the presentation of a human serum albumin (HSA)3 derived-peptide (residues 64–76K) dependent on recycling class II proteins, was reduced in DM+ B cell lines as compared with their DM- counterparts. Decreases in functional peptide presentation correlated with HLA-DM levels in the B cells. Remarkably, treatment of DM+ cells with an inhibitor of early to late endosomal transport, led to an accumulation of HLA-DM in early endosomes and a concomitant decrease in HSA peptide presentation. Thus, indicating DM is functional as it transits from early to late endosomal compartments. Peptide editing was influenced by the ratio of HLA-DO to HLA-DM in APC. These findings strongly suggest that recycling class II complexes can undergo peptide editing by HLA-DM within early endocytic compartments and that HLA-DO can modulate this ligand exchange.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Peptides

HSA peptide 64–76K (VKLVNEVTEFAKTK) and influenza hemagglutinin (HA-flu) peptide 307–319 (PKYVKQNTLKLAT) were synthesized using Fmoc technology as described (14, 15).

Cell lines

Class II null APC T2 and 6.1.6 were transduced with retroviruses to express HLA-DR4w4 (DRA1*0101; DRB1*0401). Expression of HLA-DM was restored in these cells to yield T2-DR4/DM and 6.1.6-DR4/DM (16). In contrast with their DM-negative counterparts, these lines are proficient in exogenous Ag presentation and have reduced levels of unstable class II-associated invariant chain peptide (CLIP) complexes (16). Variants of the B-lymphoblastoid cell, Sweig, 7C3, and 6H5.DM (A. Rudensky, University of Washington, Seattle, WA), were retrovirally transduced to express HLA-DR4. 7C3 cells express low DM levels relative to 6H5.DM, stably transfected to achieve high intracellular DM (17). DM expression in 6H5.DM correlates with reduced numbers of cellular class II-CLIP complexes (17). DR4-transduced cells expressing equivalent levels of surface DR4 were isolated using the HLA-DR4-specific Ab 3.5.9-13F10 and FACS. The cell lines including T cell hybridomas, 17.9 specific for DR4w4 and HSA (residues 64–76) and 50.84.17 specific for DR4w4 and HA-flu (residues 307–319) were cultivated and maintained as described (15, 16)

Ag presentation assays

Ag presentation assays were performed as described using a range of peptide concentrations (14, 15). To assess T cell activation, serially diluted cell culture supernatants were assayed for IL-2 based on HT-2 cell proliferation. For inhibitor assays, APC were pulsed with bafilomycin A1 (0.01 µM; Sigma, St. Louis, MO) 1 h before peptide addition (0.05–40 µM) and further incubated for 18 h plus drug before aldehyde fixation (0.5%) and the addition of appropriate T cells. Studies were repeated on an average of three to five times, with results from a representative experiment shown as the average of triplicate samples ± SEM. T cell proliferation in response to APC without peptide was always <1000 cpm.

Fluorescence-activated cell sorting

Cells were treated with/without 0.01 µM bafilomycin A1 for 18 h before incubation with Abs to HLA-DM (MAP1.1-DM; a gift of Dr. L. Denzin, Sloan Kettering, New York, NY), HLA-DR (L243), or isotype controls at 4°C for 30 min. Washed cells were stained with rabbit anti-mouse dichlorotriazinyl amino fluorescein (Accurate Chemical and Scientific, Westbury, NY), resuspended in 1% paraformaldehyde, and analyzed on a FACScan (BD Biosciences, Mountain View, CA). Each study was repeated at least three times.

Subcellular fractionation and immunoblotting

T2-DR4/DM cells treated with or without 0.01 µM bafilomycin A1, were then fractionated on a 15% Percoll gradient as described (14). The fractions were separated by SDS-PAGE (10%) and analyzed by Western blotting for DR (DA6.147), DM (DM-K8, gift of Dr. A. Vogt, Basel, Switzerland), and the early endosome adaptor protein AP-2 (F. Brodsky, University of California, San Francisco, CA). Localization of AP-2 in fractions 12–14 confirmed the separation of early endosomes from late endosomes and lysosomes in fractions 1–3 containing the marker enzyme, {beta}-galactosidase (14). For Sweig-derived cells, pelleted membranes were analyzed by immunoblotting with anti-DM (DM K8) or anti-DO{beta} (gift of Dr. E. Mellins, Stanford University, Stanford, CA) as described (18). These experiments were repeated three times, and the overall variance in the distribution of DM and DR among these studies was <8%.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Enhanced presentation of an exogenous peptide in the absence of HLA-DM

HLA-DM- cells are defective in Ag presentation, whereas this deficiency is corrected in DM+ cells (19). Both types of cells have been shown to present exogenous peptides efficiently to T cells (19, 20, 21). Yet, presentation of an exogenously supplied HSA peptide (residues 64–76K), was significantly enhanced in the DM- cell line (T2-DR4) compared with the same cell expressing HLA-DM (Fig. 1GoA). Similar results were observed for this peptide with the BLS cell line 6.1.6-DR4 and its DM+ counterpart (Fig. 1GoB). Reduced presentation of the HSA peptide in DM+ cells may be due to the decreased availability of MHC class II molecules in the DM-transfected cell line, as a result of DM editing of unstable peptides such as CLIP. We therefore investigated the presentation of a high affinity peptide, HA-flu (residues 307–319), which binds surface DR4 molecules (15, 22). As seen in Fig. 1GoC, only a slight reduction in HA-flu peptide presentation was observed in cells expressing abundant HLA-DM compared with DM null cells. Similar results were observed with the HA-flu peptide and 6.1.6-derived cell lines (data not shown). Studies using aldehyde-fixed APC ± DM revealed little difference in peptide binding to surface DR, in agreement with flow cytometric analysis confirming similar DR expression on these cells (data not shown). Thus, the availability of empty or accessible class II molecules alone could not explain the observed differential presentation of the HSA peptide in cells ± DM.



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  		FIGURE 1. Presentation of exogenously delivered HSA peptide was modulated by APC expression of HLA-DM. DM+/- cell lines (T2-DR4 and T2-DR4/DM (A) or 6.1.6-DR4 and 6.1.6-DR4/DM (B)) and DM low (7C3-DR4) or DM high cells (6H5.DM-DR4 (E)) were incubated overnight with HSA peptide. The extent of peptide presentation was assessed by the addition of the HSA peptide-specific T cell hybridoma, 17.9. C, APC were incubated overnight with HA-flu peptide and subsequently assessed for their ability to trigger the stimulation of 50.84.17 T cell hybridoma. The extent of presentation of the HSA peptide, but not HA-flu peptide, was linked to DM levels in the APC. D, Pelleted membranes of Sweig-derived cells were immunoblotted with DM K8 (anti-DM) and anti-DO{beta}. The DM levels were much higher in 6H5.DM-DR4 cells relative to 7C3-DR4 cells, whereas both cells expressed DO equivalently.

 
T2 cells have a deletion in the MHC locus whereas 6.1.6 cells lack a transcription factor necessary for class II gene expression (16), resulting in the loss of HLA-DO, a modulator of HLA-DM function (4, 5, 23). To establish whether DM-dependent editing of the HSA peptide occurred in the presence of physiological levels of DO, variants of a wild-type B-lymphoblastoid cell line expressing DO, DM, and DR4 were tested (17). The cells 6H5.DM-DR4 (DM high) and 7C3-DR4 (DM low) differed in their DM levels (Fig. 1GoD) but expressed equivalent amounts of HLA-DR4 and HLA-DO as ascertained by FACS staining (data not shown) and Western blots (Fig. 1GoD). The DMlow 7C3-DR4 cell presented the HSA peptide significantly better than the DMhigh 6H5.DM-DR4 cell (Fig. 1GoE). Thus, the degree of HSA peptide presentation was linked to the level of HLA-DM expressed by cells even in the presence of HLA-DO. Little if any DM was detected on the surface of these cells, suggesting that functional differences must be linked to intracellular DM pools (data not shown). The HSA epitope appears to form an unstable complex with class II DR4 molecules much like invariant chain-derived CLIP. Indeed, like CLIP, the HSA peptide can be released from cell surface DR at pH 4, whereas the binding and presentation of high affinity peptides such as the HA-flu epitope remain unperturbed (data not shown). HLA-DM has been reported to preferentially edit peptides having valine at the P1 position (24). Valine occurs at three positions in the HSA peptide, and it is tempting to speculate that one of these residues may facilitate peptide exchange by DM.

HLA-DM can edit exogenous peptides in early endosomes and the ratio of DM:DO is important in modulating this function

In contrast with other synthetic peptides, the HSA epitope examined in this study is dependent on transit through early endosomal compartments before functional class II-restricted presentation (15). To address the site of DM editing of the HSA peptide, inhibitors of endocytic transport were tested. Bafilomycin A1 is an inhibitor of vacuolar H+ ATPases that interferes with early to late endosomal transport but can also affect internalization and endocytic recycling in some cell types (25, 26). HSA peptide presentation was unaffected by bafilomycin A1 treatment of DM- APC (Fig. 2GoA), indicating that delivery of the HSA peptide to early endosomal compartments as well as recycling of the class II molecules was not disrupted by this treatment. However, treatment with bafilomycin A1 led to decreased presentation of the peptide in cells transfected with HLA-DM (6.1.6-DR4/DM and T2-DR4/DM; Fig. 2GoA), with no reduction in surface DR4. A lack of change in surface class II expression with bafilomycin has been previously reported (28). Similar results were observed with nocodazole, another inhibitor of early to late endocytic transport. Chloroquine neutralizes the acidic pH within endosomes and lysosomes without disrupting transport between these compartments, yet this drug did not alter HSA peptide presentation (data not shown). Thus, editing of the HSA peptide was localized to early endocytic compartments, because the editing was enhanced rather than ablated by treating cells with inhibitors of early to late endosomal transport.



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  		FIGURE 2. Disrupting early to late endosomal transport in APC with bafilomycin A1 leads to decreased presentation of the HSA peptide and increased levels of DM in early endosomes but does not alter surface DM expression. A, APC whether DM-DO- (T2-DR4 (a) or 6.1.6-DR4 (b)), DM+DO- (T2-DR4/DM (c), 6.1.6-DR4/DM (d)), DMlowDO+ (7C3-DR4 (e)), or DMhighDO+ (6H5.DM-DR4 (f)) were incubated with ({blacksquare}) or without ({square}) bafilomycin A1 for 1 h before HSA peptide addition and subsequent addition to 17.9 T cells. APC were incubated with 5 µM concentrations of the HSA peptide except for Sweig-derived cells, which received 40 µM. Similar results were observed over a range of peptide concentrations (1–40 µM). IL-2 secretion by the stimulated T cells was assessed as described in Materials and Methods. Data are expressed as percent of maximal response of the untreated cells with a median maximal response of 73,161 cpm and SEM of <10%. Results are representative of at least three separate experiments. B, T2-DR4/DM cells treated with ({blacksquare}) or without ({square}) 0.01 µM bafilomycin A1 for 18 h before density gradient fractionation on 15% Percoll. The fractions were separated by SDS-PAGE electrophoresis and blotted with DM K8 Ab. The percent DM was calculated by densitometric analysis. Data are representative examples of three separate experiments. C, APC (6.1.6-DR4/DM) were treated with (dark line) or without (broken line with fill) 0.01 µM bafilomycin A1 for 18 h before staining for surface DM expression with anti-DM (MAP1.1). Dotted line represents control staining of treated cells. Surface class II DR expression was unchanged by bafilomycin treatment with a mean channel fluorescence of 728 for treated cells vs 749 for untreated cells.

 
The DMlow 7C3-DR4 cells having physiological levels of DO, behaved like DM- cells in that bafilomycin A1 treatment did not enhance DM-mediated editing of the HSA peptide. Rather, the drug treatment increased the presentation of the peptide in these cells (Fig. 2GoA). By contrast, DMhighDO+ 6H5.DM-DR4 cells showed a substantial reduction in presentation of the peptide on exposure to bafilomycin A1. The ratio of HLA-DO and DM in these cells may explain these observed differences in epitope editing. Although DO levels are comparable in these cells, DM expression is >10-fold higher in 6H5.DM-DR4 (Fig. 1GoD). Studies suggest HLA-DO influences peptide loading of class II molecules by limiting HLA-DM activity at mildly acid or neutral pH (4, 5). In addition to disruption of early to late endocytic transport, bafilomycin A1 is also known to neutralize the endocytic pathway as a result of its disruption of endosomal/lysosomal proton pumps (26). Depending on the ratio of DM and DO in a compartment, a neutral pH within endosomes could affect DM activity in the presence of DO. Thus, in bafilomycin A1-treated low DM 7C3-DR4 cells, increased editing of the HSA epitope could be blocked by HLA-DO. In 6H5.DM-DR4 cells, the very high levels of DM expressed presumably overcame any effect of DO. These results therefore suggest that the DO:DM ratio may be important in enabling HLA-DO to modulate the functioning of HLA-DM and that, in the absence of DO, HLA-DM can retain its editing activity even at near neutral pH.

Although DM is found predominantly in late endosomes/prelysosomes in B cells, low levels of DM have been observed in early endocytic compartments as well as the cell surface of APC (10, 27). Bafilomycin A1 treatment of APC resulted in enhanced editing of the HSA peptide (Fig. 2GoA), suggesting DM accumulation in early endosomes after treatment with this drug. These results support a pathway of DM transit from the cell surface through early endosomes en route to mature endosomes such as MIIC. This was addressed further by subcellular fractionation. Bafilomycin A1 treatment of T2-DR4/DM cells led to an increase in DM levels in the lighter compartments (66.2 ± 7.6% DM) as compared with the untreated controls (47.8 ± 2.5; Fig. 2GoB). Disruption of early to late endosomal transport also led to an accumulation of class II molecules in the early endosomes (60 ± 7.8% HLA-DR4 in treated cells vs 50.1 ± 6.7% in untreated controls) similar to that reported by Villadangos et al. (28) for mouse splenocytes. Liu et al. (29) have suggested that DM may routinely transit to the cell surface with peptide-loaded class II MHC molecules and that rapid endocytosis of DM may represent a critical recapture step. The tyrosine motif found in the cytoplasmic tail of DM may act as a signal for this rapid internalization and sorting to endocytic compartments (30). Attempts to detect DM editing of the HSA peptide at the cell surface were negative even using direct peptide:class II binding techniques (our unpublished observation). Yet, to determine whether bafilomycin A1 triggers a redistribution of HLA-DM to the cell surface, we analyzed DM expression in cells with and without exposure to this drug. Surface Ab staining of untreated T2-DR4/DM cells revealed low levels of HLA-DM in agreement with published studies (10). A similar pattern of surface DM expression was also observed for 6.1.6-DR4/DM (Fig. 2GoC). Treatment of these cells with bafilomycin A1 did not lead to an increase in surface DM (Fig. 2GoC) in agreement with published studies demonstrating the specificity of this drug for disruption of early to late endocytic transit and supporting a rapid reinternalization of DM into early endosomes. Thus, the enhanced editing of the HSA peptide observed in bafilomycin A1-treated APC was due to the accumulation of DM within early endosomes.

In conclusion, three important findings emerge from this study: 1) our data establish that select exogenous peptides are susceptible to HLA-DM editing; 2) although the overall levels of DM in early endosomal compartments are low, editing of peptide:class II complexes in these organelles does occur, suggesting that HLA-DM can regulate the stability and half-life of surface class II peptide complexes via the recycling pathway; 3) the editing function of HLA-DM in the early or recycling endosomes is influenced by the DM:DO ratio.


   Acknowledgments
 
We thank J. Beitz for technical assistance; Dr. Dennis Zaller, Merck Research Laboratories, for T cell hybridoma lines; and Dr. C. Dunn and Dr. K. Dunn for helpful comments.


   Footnotes
 
1 This work was supported by National Institutes of Health and Phi Beta Psi. Back

2 Address correspondence and reprint requests to Dr. Janice S. Blum, Medical Science Building, Room 255, 635 Barnhill Drive, Indianapolis, IN 46202-5120. E-mail address: jblum{at}iupui.edu Back

3 Abbreviations used in this paper: HSA, human serum albumin; HA-flu, influenza hemagglutinin; CLIP, class II-associated invariant chain peptide. Back

Received for publication July 14, 2000. Accepted for publication May 23, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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A. Muntasell, M. Carrascal, L. Serradell, P. v. Veelen, F. Verreck, F. Koning, G. Raposo, J. Abian, and D. Jaraquemada
HLA-DR4 Molecules in Neuroendocrine Epithelial Cells Associate to a Heterogeneous Repertoire of Cytoplasmic and Surface Self Peptides
J. Immunol., November 1, 2002; 169(9): 5052 - 5060.
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