© The Rockefeller University Press, 0022-1007/1997/2/429/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 3, February 3, 1997 429-438
Related Leucine-based Cytoplasmic Targeting Signals in Invariant Chain and Major Histocompatibility Complex Class II Molecules Control Endocytic Presentation of Distinct Determinants in a Single Protein
Guangming Zhong,
Paola Romagnoli, and
Ronald N. Germain
From the Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892
Leucine-based signals in the cytoplasmic tail of invariant chain (Ii) control targeting of newly synthesized major histocompatibility complex class II molecules to the endocytic pathway for acquisition of antigenic peptides. Some protein determinants, however, do not require Ii for effective class II presentation, although endocytic processing is still necessary. Here we demonstrate that a dileucine-based signal in the cytoplasmic tail of the class II β chain is critical for this Ii-independent presentation. Elimination or mutation of this signal reduces the rate of re-entry of mature surface class II molecules into the endocytic pathway. Antigen presentation controlled by this signal does not require newly synthesized class II molecules and appears to involve determinants requiring only limited proteolysis for exposure, whereas the opposite is true for Ii-dependent determinants. This demonstrates that related leucine-based trafficking signals in Ii and class II control the functional presentation of protein determinants with distinct processing requirements, suggesting that the peptide binding sites of newly synthesized versus mature class II molecules are made available for antigen binding in distinct endocytic compartments under the control of these homologous cytoplasmic signals. This permits capture of protein fragments produced optimally under distinct conditions of pH and proteolytic activity.
Address correspondence to Ronald N. Germain, Lymphocyte Biology Section, Laboratory of Immunology, NIAID, NIH, Bldg 10, Rm 11N311, 10 Center Drive MSC-1892, Bethesda, MD 20892-1892.
The authors wish to thank members of the Lymphocyte Biology Section for many helpful discussions and suggestions throughout the course of this work. We also thank Drs. Jack Bennink and Jon Yewdell for their assistance with confocal microscopy, Luciano Adorini for providing critical T hybridomas, and Eric Long, Flora Castellino, and Caetano Reis e Sousa for comments on the manuscript. We also thank an anonymous reviewer for very useful suggestions for improving the original submitted manuscript.
1Abbreviations used in this paper: BFA, brefeldin A; CLIP, class II–associated invariant chain peptide; HEL, hen egg lysozyme; Ii, invariant chain; MIIC, class II–rich organelles; RBL, rat basophil leukemia cell.

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-
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-
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-
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-
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-
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-
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[Abstract]
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-
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(1999). Engagement of B Cell Receptor Regulates the Invariant Chain-Dependent MHC Class II Presentation Pathway. J. Immunol.
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[Abstract]
[Full Text]
-
Samaan, A., Thibodeau, J., Mahana, W., Castellino, F., Cazenave, P. A., Kindt, T. J.
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[Abstract]
[Full Text]
-
Wilson, N. A., Wolf, P., Ploegh, H., Ignatowicz, L., Kappler, J., Marrack, P.
(1998). Invariant Chain Can Bind MHC Class II at a Site Other Than the Peptide Binding Groove. J. Immunol.
161: 4777-4784
[Abstract]
[Full Text]
-
Castellino, F., Zappacosta, F., Coligan, J. E., Germain, R. N.
(1998). Large Protein Fragments as Substrates for Endocytic Antigen Capture by MHC Class II Molecules. J. Immunol.
161: 4048-4057
[Abstract]
[Full Text]
-
Maurer, D., Fiebiger, E., Reininger, B., Ebner, C., Petzelbauer, P., Shi, G.-P., Chapman, H. A., Stingl, G.
(1998). Fc{epsilon} Receptor I on Dendritic Cells Delivers IgE-Bound Multivalent Antigens into a Cathepsin S-Dependent Pathway of MHC Class II Presentation. J. Immunol.
161: 2731-2739
[Abstract]
[Full Text]
-
Lankar, D., Briken, V., Adler, K., Weiser, P., Cassard, S., Blank, U., Viguier, M., Bonnerot, C.
(1998). Syk Tyrosine Kinase and B Cell Antigen Receptor (BCR) Immunoglobulin-{alpha} Subunit Determine BCR-mediated Major Histocompatibility Complex Class II-restricted Antigen Presentation. JEM
188: 819-831
[Abstract]
[Full Text]
-
Thery, C., Brachet, V., Regnault, A., Rescigno, M., Ricciardi-Castagnoli, P., Bonnerot, C., Amigorena, S.
(1998). MHC Class II Transport from Lysosomal Compartments to the Cell Surface Is Determined by Stable Peptide Binding, But Not by the Cytosolic Domains of the {alpha}- and {beta}-Chains. J. Immunol.
161: 2106-2113
[Abstract]
[Full Text]
-
Chianese-Bullock, K. A., Russell, H. I., Moller, C., Gerhard, W., Monaco, J. J., Eisenlohr, L. C.
(1998). Antigen Processing of Two H2-IEd-Restricted Epitopes Is Differentially Influenced by the Structural Changes in a Viral Glycoprotein. J. Immunol.
161: 1599-1607
[Abstract]
[Full Text]
-
Delvig, A. A., Robinson, J. H.
(1998). Two T Cell Epitopes from the M5 Protein of Viable Streptococcus pyogenes Engage Different Pathways of Bacterial Antigen Processing in Mouse Macrophages. J. Immunol.
160: 5267-5272
[Abstract]
[Full Text]
-
Bikoff, E. K., Kenty, G., Van Kaer, L.
(1998). Distinct Peptide Loading Pathways for MHC Class II Molecules Associated with Alternative Ii Chain Isoforms. J. Immunol.
160: 3101-3110
[Abstract]
[Full Text]
-
Amigorena, S., Lankar, D., Briken, V., Gapin, L., Viguier, M., Bonnerot, C.
(1998). Type II and III Receptors for Immunoglobulin G (IgG) Control the Presentation of Different T Cell Epitopes from Single IgG-complexed Antigens. JEM
187: 505-515
[Abstract]
[Full Text]
-
Gapin, L., Bravo de Alba, Y., Casrouge, A., Cabaniols, J. P., Kourilsky, P., Kanellopoulos, J.
(1998). Antigen Presentation by Dendritic Cells Focuses T Cell Responses Against Immunodominant Peptides: Studies in the Hen Egg-White Lysozyme (HEL) Model1. J. Immunol.
160: 1555-1564
[Abstract]
[Full Text]
-
Lo-Man, R., Langeveld, J. P. M., Martineau, P., Hofnung, M., Meloen, R. H., Leclerc, C.
(1998). Immunodominance Does Not Result from Peptide Competition for MHC Class II Presentation. J. Immunol.
160: 1759-1766
[Abstract]
[Full Text]
-
Kenty, G., Martin, W. D., Van Kaer, L., Bikoff, E. K.
(1998). MHC Class II Expression in Double Mutant Mice Lacking Invariant Chain and DM Functions. J. Immunol.
160: 606-614
[Abstract]
[Full Text]
-
Molinari, M., Salio, M., Galli, C., Norais, N., Rappuoli, R., Lanzavecchia, A., Montecucco, C.
(1998). Selective Inhibition of Ii-dependent Antigen Presentation by Helicobacter pylori Toxin VacA. JEM
187: 135-140
[Abstract]
[Full Text]
-
Zhong, G., e Sousa, C. R., Germain, R. N.
(1997). Production, specificity, and functionality of monoclonal antibodies to specific peptide-major histocompatibility complex class II complexes formed by processing of exogenous protein. Proc. Natl. Acad. Sci. USA
94: 13856-13861
[Abstract]
[Full Text]
-
Villadangos, J. A., Riese, R. J., Peters, C., Chapman, H. A., Ploegh, H. L.
(1997). Degradation of Mouse Invariant Chain: Roles of Cathepsins S and D and the Influence of Major Histocompatibility Complex Polymorphism. JEM
186: 549-560
[Abstract]
[Full Text]
-
Brunet, A., Samaan, A., Deshaies, F., Kindt, T. J., Thibodeau, J.
(2000). Functional Characterization of a Lysosomal Sorting Motif in the Cytoplasmic Tail of HLA-DObeta. J. Biol. Chem.
275: 37062-37071
[Abstract]
[Full Text]