A functional and structural basis for TCR cross-reactivity in multiple sclerosis

Abstract

The multiple sclerosis (MS)-associated HLA major histocompatibility complex (MHC) class II alleles DRB1*1501, DRB5*0101 and DQB1*0602 are in strong linkage disequilibrium, making it difficult to determine which is the principal MS risk gene. Here we show that together the DRB1 and DRB5 loci may influence susceptibility to MS. We demonstrate that a T cell receptor (TCR) from an MS patient recognized both a DRB1*1501-restricted myelin basic protein (MBP) and DRB5*0101-restricted Epstein-Barr virus (EBV) peptide. Crystal structure determination of the DRB5*0101-EBV peptide complex revealed a marked degree of structural equivalence to the DRB1*1501-MBP peptide complex at the surface presented for TCR recognition. This provides structural evidence for molecular mimicry involving HLA molecules. The structural details suggest an explanation for the preponderance of MHC class II associations in HLA-associated diseases.

TCR β polymorphisms and multiple sclerosis

“…9,14 Given these previous findings and the knowledge of the HLA-TCR functional interaction, 24 we also tested an association, stratifying for the presence of HLA DRB1*15. The TDT results for each marker stratified for the presence of DRB1*15 in the affected offspring are given in Web Table 3 (see Supplementary Information).…”

Induction of long‐lasting multi‐specific CD8+ T cells by a four‐component DNA‐MVA/HIVA‐RENTA candidate HIV‐1 vaccine in rhesus macaques

“…The extent of CD8 + T cell cross-reactivity remains controversial with evidence both for [10][11][12][13][14][15][16][17] and against [18][19][20][21][22] its broad effectiveness. At least in the one animal tested on two occasions, we observed cross-reactivity of CD8 + T cells with 50% of tested epitope variants not present in the vaccine (Fig.…”

“…A number of studies have addressed this point with mixed results. While some studies clearly detected cross-clade-reactive HIV-1-specific CD8 + T cell responses [10][11][12][13][14][15][16][17], there is substantial evidence that CD8 + T cells can be highly sequence-specific [18][19][20][21][22]. This was best demonstrated in systematic studies employing all possible single amino acid substitutions in each position of an MHC class I epitope, which suggested that as few as one in three epitope variants was recognized by a given T cell receptor [18,23].…”

Cross-immune tolerance: conception and its potential significance on transplantation tolerance

“…24,25 Furthermore, such TCR crossreactivity involves not only the recognition of different antigenic peptides bound to the same MHC molecule, but also the recognition of antigenic peptides bound to other MHC molecules. 26 Thus, besides being antigen-specific, the TCRs also exhibit considerable plasticity in their response to antigenic stimulations.…”