Redundancy in antigen-presenting function of the HLA-DR and -DQ molecules in the multiple sclerosis-associated HLA-DR2 haplotype

Mireia Sospedra, Paolo A. Muraro, Irena Stefanová, Yingdong Zhao, Katherine Chung, Yili Li, Marc Giulianotti, Richard Simon, Roy Mariuzza, Clemencia Pinilla, Roland Martin

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1951-1961
Number of pages11
JournalJournal of Immunology
Volume176
Issue number3
DOIs
StatePublished - Feb 1 2006
Externally publishedYes

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