The role of polymorphic HLA-DR beta chain residues in presentation of viral antigens to T cells.

Abstract

SummaryThe relative importance of 11 polymorphic positions in the HLA DR701 chain in T cell recognition of foreign antigens was investigated using transfectants expressing mutant DR701 chains as APC for five rabies virus-specific T cell clones. The results indicate that multiple amino acids, located in both the fl-strands and ct-helix of DR701 in the model of a class II molecule, are involved in DR7-restricted T cell recognition of these antigens. Many of the substitutions appeared to reduce the affinity of an antigenic peptide for the mutant DR7 molecules but did not prevent binding . The heterogeneity of responses of the three G-specific T cell clones to presentation of the G11.3 peptide by several of the mutant DR7 molecules indicates that the T cell receptor (TCR) of each these clones requires a different view of the G11.3/DR7 complex and raises the possibility that the G11.3 peptide may bind to the DR7 molecule in more than one conformation . c lass 11-restricted T cell recognition offoreign antigens, a central event in the normal function of the immune system, requires the formation ofa trimolecular complex consisting ofa class II molecule, a foreign antigenic peptide, and a TCR. This is a highly specific interaction in which the TCR recognizes a unique three-dimensional conformation of the class II-peptide complex . The demonstration ofdirect binding of antigenic peptides to class II molecules has greatly facilitated the current understanding of these interactions (1, 2). Amino acid differences or polymorphisms among class II molecules play a very important role in the specificity of these interactions and are the basis for class 11-restricted T cell recognition . Although class II polymorphisms in general appear to be important in peptide binding and TCR interactions, the contributions ofindividual amino acids at polymorphic positions in these molecules are only beginning to be understood. In the murine system, several studies using mutant class II molecules generated by site-directed mutagenesis have provided insight into the contributions of individual amino acids in these molecules to restricted recognition of foreign antigens by T cells (3-8) . However, similar analyses of human class II molecules have not been reported . Elucidation of the ways in which HLA class II polymorphisms influence these complex interactions will have important implications for understanding the basis for the association of certain class 11 alleles with specific diseases and for the development of synthetic peptide vaccines.The recent description of a hypothetical model of MHC class II molecules (9), extrapolated from the crystal structure of a class I molecule (10, 11), has been very important in shaping the current understanding of the contribution ofthe class II molecule to T cell recognition . The model predicts that the antigen binding site or groove is formed by the membrane distal al and 01 domains ofclass II molecules that fold to form a platform of 0-strands which is topped by two cxhelices, one formed by a portion ...

HLA‐DPp residue 69 plays a crucial role in allorecognition

“…The second explanation is more likely, since Chiu et al (39) predicted this position interacting with a DP2 peptide. Our data support HLA-DP allorecognition, a fact previously described for DR-restricted T-cell recognition (15,49): polymorphic residues on the floor of class II molecules affect T-cell recognition less frequently than substitutions in the ahelix. Thus, we could expect that polymorphic positions on the floor contribute to T-cell allorecognition to a lesser extent than residues in the a-helix.…”

Pocket 4 of the HLA-DR(α,β 1*0401) molecule is a major determinant of T cells recognition of peptide.

“…This discrepancy was surprising, based on the distribution of presumably functionally important polymorphic residue in both the ~ strands and the c~ helix of class II molecules. Similar results, with frequent effects on T cell recognition by substitutions at multiple positions on the DIL8 chain helix and infrequent effects by substitutions in the floor, were observed in studies of other DR molecules and antigen systems that used the same DRB mutagenesis strategy: DR1restricted recognition of pertussis toxin (13) and DR7restricted recognition of rabies antigen and HA307-19 (7,22). It is important to note that we have obtained similar results with DRB mutants and T cells that recognize a promiscuous peptide, such as HA307-19, and a monogamous peptide, such as p30-42 of pertussis toxin.…”

“…cDNA clones encoding full-length HLA-DR c~ or B chains in the pcD expression vector (17) were used: DRA (18), DRBI*0401, DRBI*0402, DRBI*0403, DRBI*0404, DRBI*0405 (obtained from Peter Gregersen, North Shore University Hospital, Manhasset, NY) (19), and DRBI*0101 (American Type Culture Collection [ATCC], Rockville, MD) (20). Site-directed mutagenesis of the DRA and DR(B1*0401) cDNAs was performed by the PCR overlap extension method (21), and the mutants were sequenced to confirm the presence of the mutation and the absence of miscorporation as described (22).…”

Structure of a Complex of the Human α/β T Cell Receptor (TCR) HA1.7, Influenza Hemagglutinin Peptide, and Major Histocompatibility Complex Class II Molecule, HLA-DR4 (DRA0101 and DRB10401)

“…The recognition of a peptide/MHC pair by a TCR usually depends on the sequence of the antigen peptide and the MHC molecule at those positions that are directly contacted by the TCR ( 34 , 45 – 49 ). Data also suggest that the antigenic properties of the pMHC surface can be modulated by residues not in direct contact by the TCR ( 34 , 49 – 55 ) (for a review, see reference 56 ). The conformation and antigenicity of the bound peptide is not only strongly influenced by MHC residues that form the peptide binding pockets, but also by the peptide anchors that point into these pockets.…”