Conserved and variable structures in HLA class I molecules: a review.

Amino acid sequences and structural data on HLA class I molecules are now available, making possible a comparison of the serological and structural definitions of allelic series. 1) A hierarchy of differences between molecules is observed. Certain molecules show a low level of differences (1.2% of amino acids) and represent variants of original molecules. Other molecules are recombinants derived from two parent molecules (2.5% difference). Original molecules from an allelic series have a higher level of difference (7.6%). Maximum differences (13.5%) are observed between products from different loci. Serologically related specificities (cross-reacting groups) show a relatively low level of difference (6.4%). 2) In most specificities an exclusive residue can be considered as responsible for the formation of a serologically recognized determinant. Certain specificities do not have an exclusive residue; they can then be characterized either by a unique determinant made by the association of several non-exclusive residues, or by an unique association of several non-exclusive (shared) determinants. There is a significant correlation between the absence of an exclusive residue and the absence of monoclonal antibodies recognizing certain specificities. This suggests two kinds of definition of serological specificities, either by a single exclusive determinant (monotopic recognition) or by several shared determinants (polytopic recognition). Private and public specificities are recognized at the structural level. T-cell receptor (TCR) recognizes either a xenogeneic peptide in the context of self HLA molecules (restricted CTL [Cytotoxic T Lymphocyte]), or allogeneic HLA molecules. Determinants recognized by CTL (restricted or allogeneic) on HLA molecules have been identified. It is not possible to ascertain whether determinants recognized by antibodies and TCRs are identical, but they are probably very similar. 3) HLA class I molecule is made of 75% conserved residues (mostly in the alpha 3 and beta 2-m domains) and of 25% variable residues (mostly in the alpha 1 + alpha 2 domains). Conserved residues maintain the general shape of the molecule, its outward orientation on the cell membrane, its association with T cells CD8 molecule, and the structure of the peptide binding site, a groove at the top of molecule. Variable residues are responsible for the capacity of each molecule to bind and to present a large number of different peptides to the TCR. Each molecule carries several (3-10?) variable sites; certain are localized into the groove and are recognition sites while others, more exposed on the surface of the molecule, are sites recognized by TCRs and antibodies. Both conserved and variable regions are necessary to the function of the HLA molecule.