Identification of the cellular mechanisms responsible for the generation of particular HLA-DR epitopes

Abstract

HLA class II/peptide complexes (pHLA-II), organized into microdomains on the surface of antigen presenting cells (APCs) or on APC-secreted exosomes, engage CD4+ T cells for immune recognition. The association of the HLA-II alleles DRB1*0401/0404 with rheumatoid arthritis may be due to their propensity to present self-peptides for immune recognition. pHLA-II presentation on APCs is largely determined by HLA-DM, an intracellular chaperone, and its negative regulator, HLA-DO. Previously described DRB1*04-restricted epitopes (D11-0401, D13-0401, and D13-0404) were found dependent, sensitive, and resistant, respectively, to HLA-DM activity. The aims of this study were to determine whether (a) HLA-DO affects epitope expression; (b) cell surface microdomains concentrate these epitopes; and (c) exosomes express these epitopes. Key findings include: HLA-DO appears not essential, but its role in optimal epitope expression may be cell-context dependent; lipid raft disruption abrogated only the DM-dependent D11-0401epitope; exosomal expression of these epitopes was cell specific and independent of their cell surface expression. Altogether, this study has enhanced our knowledge of DM-dependent, -sensitive, and -resistant epitopes on rheumatoid arthritis-associated pHLA-DRB1*04 molecules.