Identification of T cell receptor recognition residues for a viral peptide presented by HLA B27

Abstract

The fine specificity of T cell recognition of peptide analogues of the influenza nucleoprotein epitope, NP 383-391 SRYWAIRTR, was studied using HLA B27-restricted influenza-specific cytotoxic T cell (CTL) clones, of defined T cell receptor (TcR) usage, derived from unrelated individuals following natural infection. Even conservative amino acid substitutions of the peptide residues P4, P7 and P8 influenced CTL recognition. These side chains are probably directly contacted by the TcR. CTL clones which used the TcR V alpha 14 gene segment (but not those using TcR V alpha 12) were also sensitive to P1 substitutions, suggesting that the TcR alpha chain of these clones lies over the N terminus of bound peptide, and that the "footprint" of certain TcR can span all exposed residues of a peptide bound to a major histocompatibility complex class I molecule. These results, taken together with previous structural and functional data, suggest that, for nonamer peptides bound to HLA B27, P1, P4 and P8 are "flag" residues with TcR-accessible side chains.

Critical Role of Endoplasmic Reticulum Aminopeptidase 1 in Determining the Length and Sequence of Peptides Bound and Presented by HLA–B27

“…Therefore, both ERAP1 silencing and ASprotective polymorphisms can lead to similar changes in the HLA-B27-bound peptides. Notably, P1 residue changes in an HLA-B27-bound epitope have been previously shown to significantly influence recognition by the T cell receptor of CTL (40).…”

Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA‐B*2705

“…Implications for T cell recognition of HLA-B27-peptide complexes, evidence from the HLA-B*2705-flu structure Although previous functional studies showed that changes to the flu P7R side chain influenced recognition by CTL clones without affecting binding by HLA-B*2705 [15], the P7R side chain has been buried in the binding groove for all previous structures described. Thus the structure of the B*2705-flu complex (Fig.…”

“…Systematic substitution of amino acids in the flu peptide has shown that positions 1, 4, 7 and 8 are most sensitive to recognition by clonotypic immunodominant BV7/AV12 or 14 receptors [15]. P1, however, shows a reduction in responses only when substituted with a bulky R, K or Y side chain.…”

“…Additionally, site-directed mutagenesis of the TCR CDR3 loops of one of these TCR molecules showed that the Y101a, which is highly conserved between clones, was essential for functional recognition [14]. The exposed P4W side chain has previously been shown to be critical for recognition by CTL clones [15]. It has been suggested that this TCR tyrosine may interact via hydrophobic or ring-stacking interactions with the peptide P4 tryptophan when complexed to peptide-MHC [14].…”

“…Mutagenesis has shown the CDR3a Y101 residue is critical for recognition of HLA-B*2705-flu [14]. HLA-B*2705-flu-specific T cell clones are sensitive to alterations in peptide side chain at positions 4, 7 and 8, and to the introduction of a K at P1 [15]. Thus substitution of the wild-type peptide P4W for a Y resulted in a substantial reduction, and substitution to F in a complete loss, of recognition for three out of four CTL clones [15].…”