HLA-A2 Allorecognition and Subtype Diversification

Analysis of structure-function relationships in HLA class I molecules has traditionally taken advantage of the characterization of subtypes of serologically defined antigens that are differentially recognized by cytotoxic T lymphocytes (CTL). Study of these subtypes has allowed the mapping of amino acid residues in the HLA molecule that determine the specificity of recognition by CTL (1). These functional positions are mainly located in the antigen binding site and alter both self-restricted and allospecific CTL recognition. As many of these changes are located in the 8-pleated sheet floor of the groove, and presumably have no direct access to interaction with T cell receptors (TCR) (2), this has suggested the participation of endogenous peptides in allospecific T cell recognition. Characterization of new subtypes also provides information on the genetic mechanisms generating class I polymorphism and on the rules governing HLA diversification (1). In this report we summarize recent work from our lab, concerning the analysis of HLA-A2 antigens expressed on cells that are differentially recognized by allospecific CTL (3), and of HLAA2 variants defined by isoelectric focusing (IEF) (4, 5).