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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
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.
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