The Journal of Experimental Medicine
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© 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

Articles

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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