HLA-DM negatively regulates HLA-DR4-restricted collagen pathogenic peptide presentation and T cell recognition

Shereen Amria, Laela M. Hajiaghamohseni, Caroline Harbeson, Dan Zhao, Oliver Goldstein, Janice S. Blum, Azizul Haque

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Rheumatoid arthritis, an autoimmune disease, is significantly associated with the HLA class II allele HLA-DR4. While the etiology of rheumatoid arthritis remains unknown, type II collagen (CII) is a candidate autoantigen. An immunodominant pathogenic epitope from this autoantigen, CII261-273, which binds to HLA-DR4 and activates CD4+ T cells, has been identified. The non-classical class II antigen, HLA-DM, is also a key component of class II antigen presentation pathways influencing peptide presentation by HLA-DR molecules expressed on professional antigen-presenting cells (APC). Here, we investigated whether the HLA-DR4-restricted presentation of the pathogenic CII261-273 epitope was regulated by HLA-DM expression in APC. We show that APC lacking HLA-DM efficiently display the CII261-273 peptide/epitope to activate CD4+ T cells, and that presentation of this peptide is modulated dependent on the level of HLA-DM expression in APC. Mechanistic studies demonstrated that the CII261-273 peptide is internalized by APC and edited by HLADM molecules in the recycling pathway, inhibiting peptide presentation and T cell recognition. These findings suggest that HLA-DM expression in APC controls class II-mediated CII261-273 peptide/epitope presentation and regulates CD4+ T cell responses to this self epitope, thus potentially influencing CII-dependent autoimmunity.

Original languageEnglish (US)
Pages (from-to)1961-1970
Number of pages10
JournalEuropean Journal of Immunology
Volume38
Issue number7
DOIs
StatePublished - Jul 1 2008

Keywords

  • CD4 T cells
  • HLA-DM
  • HLA-DR
  • Peptide presentation
  • Type II collagen

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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