Polymorphic DQ alpha and DQ beta interactions dictate HLA class II determinants of allo-recognition.

Abstract

T cell activation mediated by the TCR is triggered by a complex of an antigenic peptide with a cell surface protein encoded by the MHC. The specific control of the trimolecular interaction between a particular antigen, MHC molecule, and TCR follows a set of genetically programmed parameters . MHC polymorphisms regulate one of these parameters, termed MHC restriction, by which some MHC alleles form "permissive" complexes that permit T cell response, and other MHC alleles do not. Recent studies using murine class II MHC molecules (1-2) have demonstrated that the act of binding a peptide is necessary, but not always sufficient to trigger potentially reactive T cells; presumably, precise structural interactions between amino acids on the peptide and on the class II molecule itself are crucial for recognition. Structural variation among class II molecules can be critically important for this function . In the example of the H-26 "12 mouse, three amino acid substitutions in the class II Ia (3 chain distinguish the bm12 strain from the parental B6 strain, and apparently confer a wide variety of distinct immunologic characteristics, including alloreactivity against the parental B6, differential responsiveness to defined antigenic peptides, and differential susceptibility to experimentally induced myasthenia gravis (3-5).As the bm12 mouse example illustrates, specific substitutions in class 11 0 chains may have dramatic consequences for immune function . Among human class II molecules, both the class II a and the class 11 0 chains in functional class II dimers potentially contribute structural variation affecting function, particularly at the HLA-DQ locus, where both a and a genes are highly polymorphic. Structural models of recognition events involving HLA class II molecules suggest that polymorphic sites on a and /3 chains potentially interact with each other, with peptide, and with TCR (6-7).To evaluate the fine structural requirements ofthis interaction, we analyzed human T cell-MHC interactions in vitro by evaluating the effects of specific molecular substitutions within the class II HLA-DQ a and /3 chain components . We have previously described the use of site-directed mutagenesis on cloned human MHC genes,

DRB1*0403 Protects Against IDDM in Caucasians With the High-Risk Heterozygous DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 Genotype

“…Synergism between DR3 and DR4 haplotypes in Caucasian IDDM patients seems to be caused (at least in part) by Zrans-complementation of closely linked DQA1 and DQB1 susceptibility alleles (20,21). Confirming previous studies (8)(9)(10), our data also clearly show that the major contribution of DR4 haplotypes to genetic susceptibility derives from DQB 1*0302, which was found in virtually all IDDM patients while one-third of the control subjects were DQBl*0302-negative.…”

Heterogeneity inHLA-DR2-relatedDR, DQ haplotypes in eight populations of Asia-Oceania

“…Transfection studies (Kwok et al 1990), analysis of mutant alleles (Mellins et al 1990), and analysis of reaction patterns of monoclonal antibodies have permitted assignment of some serological determinants and some T-cell recognition epitopes to precise amino acid sequences in HLA class II alleles. An alternative approach is analysis of different populations with different HLA class II linkage arrangements.…”

MHC Class-II Molecules and Autoimmunity

“…Such dimers have been shown to exist in diabetics (20). In transfection studies such class-II dimers confer distinct T-cell recognition properties (19,21). Never theless, since most diabetics are not heterozygous for DR3/4, such inter action is unlikely to be an essential part of the disease-associated pathway.…”

“…Using site-directed mutagenesis, Kwok et al (19,25) have dem onstrated that the major serologic specifi cities associated with DQ3.2 correspond to amino acid residues at codon 45, and that allorecognition by T-cell clones is heavily infl uenced by multiple polymorphic sites on the f3 chain. In these studies, the residue at codon 57 contributes in a significant way to interactions between polymorphic DQIX chains and recognition of specifi c sites on the f3 chain by different T-cell clones.…”