Redundancy in antigen-presenting function of the HLA-DR and -DQ molecules in the multiple sclerosis-associated HLA-DR2 haplotype.
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.
Sospedra
Mireia
M
Cellular Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
Muraro
Paolo A
PA
Stefanová
Irena
I
Zhao
Yingdong
Y
Chung
Katherine
K
Li
Yili
Y
Giulianotti
Marc
M
Simon
Richard
R
Mariuzza
Roy
R
Pinilla
Clemencia
C
Martin
Roland
R
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
D006683:HLA-DQ Antigens; D015802:HLA-DR2 Antigen; D010455:Peptides