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ERAP1-dependent extreme antigen processing efficacy can govern MHC class I expression hierarchy.

Jacqueline Leib1, Emmanuelle Waeckel-Énée1, Sylvie Fabrega2

  • 1Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, Paris, France.

Journal of Immunology (Baltimore, Md. : 1950)
|March 28, 2025
PubMed
Summary

Researchers developed a flow cytometry assay to test inhibitors of human aminopeptidases ERAP1, ERAP2, and IRAP. This assay aids in developing therapies for autoimmune diseases and cancer by assessing peptide trimming and MHC-I presentation.

Keywords:
MHC class Iantigen presentationantigen processingendoplasmic reticulum aminopeptidaseovalbuminpeptide trimming

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Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • Major histocompatibility complex (MHC) class I molecules present intracellular peptides to CD8+ T cells, crucial for immune surveillance.
  • The density of peptide-MHC-I complexes on cell surfaces influences T cell responses and depends on efficient intracellular peptide generation.
  • Human aminopeptidases ERAP1, ERAP2, and IRAP are critical for the final trimming of peptides for MHC-I presentation, and their genetic variations are linked to autoimmune diseases and cancers.

Purpose of the Study:

  • To develop a quantitative flow cytometry assay for assessing the effects of small molecule inhibitors on peptide trimming by ERAP1, ERAP2, and IRAP.
  • To evaluate the assay's utility in both endogenous MHC-I processing and cross-presentation pathways.
  • To identify selective inhibitors targeting these aminopeptidases for potential therapeutic applications in autoimmunity and oncology.

Main Methods:

  • Development of a flow cytometry-based assay for quantitative assessment of peptide trimming by ERAP enzymes.
  • Application of the assay to evaluate selective inhibitor effects on peptide-MHC-I complex formation.
  • Utilizing the assay to measure both specific peptide-MHC complexes and bulk MHC-I surface levels.

Main Results:

  • Successful development of a flow cytometry assay for evaluating selective inhibitor effects on peptide trimming.
  • Identification of a selective ERAP2 inhibitor using the developed assay.
  • Demonstration that inhibitor effects can be monitored by assessing specific peptide-MHC complexes or total MHC-I surface levels.

Conclusions:

  • The developed assay provides a valuable tool for testing small molecule inhibitors targeting ERAP enzymes in the context of MHC-I antigen presentation.
  • ERAP enzyme activity significantly influences the immunopeptidomic profile of cells, impacting CD8+ T cell recognition.
  • Understanding ERAP-mediated peptide trimming is crucial for elucidating the genetic associations of ERAP polymorphism with autoimmune diseases and for developing targeted therapies.