HLA-DM negatively regulates HLA-DR4-restricted collagen pathogenic peptide presentation and T cell recognition.
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.
Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
Shereen
S
Amria
Laela M
LM
Hajiaghamohseni
Caroline
C
Harbeson
Dan
D
Zhao
Oliver
O
Goldstein
Janice S
JS
Blum
Azizul
A
Haque
D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D024043:Collagen Type II / Q000276:immunology* / Q000378:metabolism; D006681:HLA-D Antigens / Q000276:immunology* / Q000378:metabolism; D015804:HLA-DR4 Antigen / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D010446:Peptide Fragments / Q000276:immunology
D001324:Autoantigens; D024043:Collagen Type II; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D015804:HLA-DR4 Antigen; D010446:Peptide Fragments