Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells

J Exp Med. 2011 Dec 19;208(13):2625-32. doi: 10.1084/jem.20110640. Epub 2011 Dec 12.

Abstract

Antibody responses to citrullinated self-proteins are found in autoimmunities, particularly in rheumatoid arthritis, where they serve as a diagnostic indicator. We show here that processing of the protein hen egg-white lysozyme (HEL) resulted in citrullination of peptides presented on class II MHC molecules by antigen-presenting cells. The presentation of the citrullinated peptides but not of the unmodified peptides was associated with autophagy. Dendritic cells (DCs), macrophages, and thymic DCs presented citrullinated peptides constitutively. Their treatment with 3-methyladenine (3MA) blocked presentation of citrullinated HEL peptides, but presentation of unmodified peptides was not affected. Presentation of citrullinated peptides was not detected on B cells or B lymphoma cells under normal culture conditions. In B cells, engagement of the B cell antigen receptor was required for presentation of the citrullinated peptides, also inhibited by 3MA. B lymphoma-expressing HEL cells presented citrullinated peptides only after brief serum starvation. This presentation was reduced by 3MA or by reduction in Atg5 expression. Presentation of the unmodified peptides was not changed. The findings indicate a linkage between autophagy and autoreactivity through the generation of this neo-epitope.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Animals
  • Antigen Presentation / drug effects
  • Antigen Presentation / immunology*
  • Antigen-Presenting Cells / immunology*
  • Autophagy-Related Protein 5
  • B-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Citrulline*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Humans
  • Lymphoma, B-Cell / immunology
  • Mice
  • Microtubule-Associated Proteins / immunology
  • Peptides / immunology*
  • Receptors, Antigen, B-Cell / immunology

Substances

  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Microtubule-Associated Proteins
  • Peptides
  • Receptors, Antigen, B-Cell
  • Citrulline
  • 3-methyladenine
  • Adenine