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

Sospedra, M, Muraro, PA, Stefanová, I et al. (2006). Redundancy in antigen-presenting function of the HLA-DR and -DQ molecules in the multiple sclerosis-associated HLA-DR2 haplotype . JOURNAL OF IMMUNOLOGY, 176(3), 1951-1961. 10.4049/jimmunol.176.3.1951

cited authors

  • Sospedra, M; Muraro, PA; Stefanová, I; Zhao, Y; Chung, K; Li, Y; Giulianotti, M; Simon, R; Mariuzza, R; Pinilla, C; Martin, R

authors

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. Copyright © 2006 by The American Association of Immunologists, Inc.

publication date

  • February 1, 2006

published in

Digital Object Identifier (DOI)

start page

  • 1951

end page

  • 1961

volume

  • 176

issue

  • 3