Ralph T. Kubo

Definition of an HLA-A3-like supermotif demonstrates the overlapping peptide-binding repertoires of common HLA molecules

An HLA-A3-like supertype (minimally comprised of products from the HLA class I alleles A3, A11, A31, A*3301, and A*6801) has been defined on the basis of (a) structural similarities in the antigen-binding groove, (b) shared main anchor peptide-binding motifs, (c) the identification of peptides cross-reacting with most or all of these molecules, and (d) the definition of an A3-like supermotif that efficiently predicts highly cross-reactive peptides. Detailed secondary anchor maps for A3, A11, A31, A*3301, and A*6801 are also described. The biologic relevance of the A3-like supertype is indicated by the fact that high frequencies of the A3-like supertype alleles are conserved in all major ethnic groups. Because A3-like supertype alleles are found in most major HLA evolutionary lineages, possibly a reflection of common ancestry, the A3-like supermotif might in fact represent a primeval human HLA class I peptide-binding specificity. It is also possible that these phenomena might be related to optimal exploitation of the peptide specificity by human TAP molecules. The grouping of HLA alleles into supertypes on the basis of their overlapping peptide-binding repertoires represents an alternative to serologic or phylogenetic classification.

Design and Testing of Peptide-Based Cytotoxic T-Cell-Mediated Immunotherapeutics to Treat Infectious Diseases and Cancer

Cytotoxic T lymphocytes (CTLs) have been implicated in the control and elimination of various viral and bacterial infections, tumors, and some parasitic diseases. CTLs that are characterized by the presence of the CD8 antigen generally recognize peptide fragments derived from intracellular processing of various antigens in the form of a complex with MHC class I molecules expressed on the cell surface (Germain and Margulies, 1993). This recognition may result in the lysis of the cell bearing the MHC-peptide antigen complex in an antigen-specific, MHC-restricted manner (Germain and Margulies, 1993). In addition, CTLs also generate a number of different lymphokines including gamma interferon (IFN-γ) and tumor necrosis factor (TNF), which are either directly cytolytic, regulate viral replication, or function to amplify the ongoing immune response (van der Bruggen and Van den Eynde, 1992; Jassoy et al., 1993; Rosenberg et al., 1988).

Analysis of MHC-Specific Peptide Motifs

Vertebrate immune responses hinge on T cell receptor (TCR)-mediated recognition of antigenic peptides bound to polymorphic class I and class II molecules of the Major Histocompatibility Complex (MHC). The polymorphism that exists at MHC class I and class II loci has no known parallel in the vertebrate genome. The desire to understand the origins and functional consequences of MHC polymorphism has engaged and challenged immunologists, molecular biologists, and population geneticists alike over the past 50 years. It is only recently that extensive structural and biochemical analyses have given way to “enlightenment” at the molecular level and provided fresh insights into MHC polymorphism and its functional concomitants. For both class I and class II molecules, structure and function are inextricably linked through the binding of peptides, and polymorphism is now understood in terms of its contribution to the peptide binding specificities (“motifs”) associated with various MHC allomorphs.