title: Redundancy in antigen-presenting function of the HLA-DR and -DQ molecules in the multiple sclerosis-associated HLA-DR2 haplotype.
abstract: The three HLA class II alleles of the DR2 haplotype, DRB1*1501, DRB5*0101, and DQB1*0602, are in strong linkage disequilibrium and confer most of the genetic risk to multiple sclerosis. Functional redundancy in Ag presentation by these class II molecules would allow recognition by a single TCR of identical peptides with the different restriction elements, facilitating T cell activation and providing one explanation how a disease-associated HLA haplotype could be linked to a CD4+ T cell-mediated autoimmune disease. Using combinatorial peptide libraries and B cell lines expressing single HLA-DR/DQ molecules, we show that two of five in vivo-expanded and likely disease-relevant, cross-reactive cerebrospinal fluid-infiltrating T cell clones use multiple disease-associated HLA class II molecules as restriction elements. One of these T cell clones recognizes >30 identical foreign and human peptides using all DR and DQ molecules of the multiple sclerosis-associated DR2 haplotype. A T cell signaling machinery tuned for efficient responses to weak ligands together with structural features of the TCR-HLA/peptide complex result in this promiscuous HLA class II restriction.
authors.affiliation: Cellular Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Mireia
authors.initials: M
authors.lastname: Sospedra
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Muraro
authors.forename: Irena
authors.initials: I
authors.lastname: Stefanová
authors.forename: Yingdong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Katherine
authors.initials: K
authors.lastname: Chung
authors.forename: Yili
authors.initials: Y
authors.lastname: Li
authors.forename: Marc
authors.initials: M
authors.lastname: Giulianotti
authors.forename: Richard
authors.initials: R
authors.lastname: Simon
authors.forename: Roy
authors.initials: R
authors.lastname: Mariuzza
authors.forename: Clemencia
authors.initials: C
authors.lastname: Pinilla
authors.forename: Roland
authors.initials: R
authors.lastname: Martin
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002999:Clone Cells; D006683:HLA-DQ Antigens / Q000276:immunology* / Q000378:metabolism; D015802:HLA-DR2 Antigen / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D020014:K562 Cells; D008969:Molecular Sequence Data; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology*; D010455:Peptides / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D006683:HLA-DQ Antigens; D015802:HLA-DR2 Antigen; D010455:Peptides