THE STRUCTURAL BASIS OF MHC CONTROL OF COLLAGEN-INDUCED ARTHRITIS - BINDING OF THE IMMUNODOMINANT TYPE-II COLLAGEN 256-270 GLYCOPEPTIDE TO H-2A(Q) AND H-2A(P) MOLECULES

The A(q) major histocompatibility complex (MHC) class II molecule is a ssociated with suscept ibility to murine collagen-induced arthritis (C IA), whereas the closely related H-2A(p) molecule is not. To understan d the molecular basis for this difference, we have analyzed the abilit y of H-2A(q) and H-2A(p) molecules (referred to as A(q) and A(p)) to b ind and present collagen type II (CII)-derived glycosylated and non-gl ycosylated peptides. T cell clones specific for the immunodominant CII 256-270 peptide and restricted to both A(q) and A(p) molecules were i dentified, When these clones were incubated with CII protein and eithe r A(q)- or A(p)-expressing antigen-presenting cells (APC), only A(q)-e xpressing APC were able to induce stimulation. With the use of A(beta) transgenic mice this could be shown to be solely dependent on the MHC class II molecule itself and to be independent of other MHC-or non-MH C genes. Peptide binding studies were performed using affinity-purifie d MHC class II molecules. The CII 256-270 peptide bound with lower aff inity to the A(p) molecule than to the A(q) molecule. Using a set of a lanine-substituted CII 256-270 peptides, MHC class II and T cell recep tor (TCR) contacts were identified. Mainly the side chains of isoleuci ne 260 and phenylalanine 263 were used for binding both the A(q) and A (p) molecule, i.e. the peptide was orientated similarly in the binding clefts. The major TCR contact amino acids were lysine 264, which can be posttranslotionally modified, and glutamic acid 266, which is the o nly amino acid in the heterologous peptide which differs from the mous e sequence. Glycosylation at positions 264 and 270 of the CII 256-270 peptide did not change the anchor positions used for binding to the A( q) or A(p) molecules. The autologous form of the peptide (with asparti c acid at position 266) bound with lower affinity to the A(q) molecule as compared with the heterologous peptide. The variable affinity disp layed by the immunodominant CII 256-270 peptide for different MHC clas s II molecules, the identification of MHC and TCR contacts and the sig nificance of glycosylation of these have important implications for th e understanding of the molecular basis for inherited MHC class It-asso ciated susceptibility to CIA and in turn, for development of novel tre atment strategies in this disease.