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Distinct antigen MHC class II complexes generated by separate processing pathways

R Lindner1, E R Unanue

  • 1Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.

The EMBO Journal
|December 16, 1996
PubMed
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MHC class II molecules present antigens. This study reveals a novel pathway where full-length protein antigens, not just peptides, can bind MHC class II molecules, challenging existing models of antigen processing.

Area of Science:

  • Immunology
  • Molecular Biology
  • Protein Biochemistry

Background:

  • The Major Histocompatibility Complex (MHC) class II peptide-binding groove is open-ended, allowing for various ligand lengths.
  • Antigen presentation by MHC class II molecules is crucial for adaptive immunity, involving peptide processing and loading.

Purpose of the Study:

  • To investigate the processing and presentation of a partially folded protein antigen (*HEL) by MHC class II molecules.
  • To elucidate the pathways involved in the formation of MHC class II-antigen complexes.
  • To determine if full-length proteins can be presented by MHC class II molecules.

Main Methods:

  • Complex formation between purified MHC class II molecule I-Ak (Ak) and hen egg lysozyme (*HEL).
  • Detection of complexes on antigen-presenting cells (APCs) and analysis of their stability (SDS-stable vs. SDS-unstable).

Related Experiment Videos

  • Investigation of intracellular processing compartments and the role of HLA-DM and proteases.

    • Main Results:

    • Partially folded *HEL formed SDS-unstable complexes with Ak on APCs, which were transient after endocytosis.
    • Intracellular processing yielded SDS-stable Ak complexes containing *HEL peptides and, unexpectedly, full-length *HEL.
    • Full-length *HEL association occurred via an alternative pathway requiring mature class II molecules, independent of HLA-DM and proteases, and involved endosomal Ak reacting with endocytosed *HEL.

    Conclusions:

    • MHC class II molecules can present full-length protein antigens, not solely peptides, representing a novel antigen processing pathway.
    • Two distinct MHC class II loading pathways exist: one for peptides and another for full-length proteins.
    • This discovery fundamentally alters our understanding of antigen processing and presentation by MHC class II molecules.