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MHC molecules are key players in the immune response, enabling T cells to recognize and respond to specific antigens. They are present on the surface of all nucleated cells in the body and are instrumental in presenting antigens to T cells and activating them. T cells recognize the MHC-antigen complex and initiate an immune response. MHC class I and MHC class II are two main types of MHC molecules, each associated with a distinct antigen processing pathway.
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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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An antigen is any substance the immune system identifies as foreign and potentially harmful to the body, prompting an immune response. Antigens have two functional properties: immunogenicity and reactivity. Immunogenicity is the ability of an antigen to stimulate a specific immune response. At the same time, reactivity describes the antigen's ability to react with the cells and antibodies produced in response to it.
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Purification of the Membrane Compartment for Endoplasmic Reticulum-associated Degradation of Exogenous Antigens in Cross-presentation
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WDFY4-dependent cross-presentation proceeds via a vacuolar antigen-processing route.

J Luke Postoak1, Alyssa Koch1, Sicong Shan1

  • 1Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110.

Proceedings of the National Academy of Sciences of the United States of America
|December 9, 2025
PubMed
Summary
This summary is machine-generated.

Cross-presentation by dendritic cells (cDC1) is TAP-dependent, not for antigen processing, but for MHC-I trafficking. This finding challenges existing models of antigen presentation.

Keywords:
antigen processingcross-presentationdendritic cells

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Area of Science:

  • Immunology
  • Cell Biology

Background:

  • The mechanism of antigen cross-presentation by type I conventional dendritic cells (cDC1) is debated.
  • One model suggests antigen processing in the cytosol after phagolysosome escape, requiring proteasomal degradation and TAP-dependent ER entry.
  • An alternative model proposes antigen processing within endocytic vesicles.

Purpose of the Study:

  • To investigate the role of the Transporter associated with Antigen Processing (TAP) in cDC1 cross-presentation.
  • To elucidate the intracellular trafficking pathway of MHC class I (MHC-I) molecules during cross-presentation.

Main Methods:

  • Utilized TAP-deficient cDC1 to assess cross-presentation efficiency.
  • Tracked MHC-I molecule trafficking within dendritic cells.

Main Results:

  • Demonstrated that cross-presentation by cDC1 is TAP-dependent.
  • Showed that TAP is crucial for the proper trafficking of MHC-I molecules.
  • Identified a post-Golgi compartment as the site for MHC-I loading during cross-presentation, potentially independent of TAP.

Conclusions:

  • Re-evaluated the role of TAP in cDC1 cross-presentation, shifting focus from antigen processing to MHC-I trafficking.
  • Proposed a model where TAP facilitates MHC-I transport to a specific compartment for loading, independent of antigen peptide supply via TAP.