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

Eur J Immunol. 2008 Jul;38(7):1961-70. doi: 10.1002/eji.200738100.

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, CII(261-273), 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 CII(261-273) epitope was regulated by HLA-DM expression in APC. We show that APC lacking HLA-DM efficiently display the CII(261-273) 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 CII(261-273) peptide is internalized by APC and edited by HLA-DM 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 CII(261-273) peptide/epitope presentation and regulates CD4+ T cell responses to this self epitope, thus potentially influencing CII-dependent autoimmunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen Presentation*
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / metabolism
  • Autoantigens / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Line
  • Collagen Type II / immunology*
  • Collagen Type II / metabolism
  • HLA-D Antigens / immunology*
  • HLA-D Antigens / metabolism
  • HLA-DR4 Antigen / immunology*
  • HLA-DR4 Antigen / metabolism
  • Humans
  • Peptide Fragments / immunology

Substances

  • Autoantigens
  • Collagen Type II
  • HLA-D Antigens
  • HLA-DM antigens
  • HLA-DR4 Antigen
  • Peptide Fragments