Binding of immunogenic peptides to Ia histocompatibility molecules

Abstract

Most cellular interactions essential for the development of an immune response involve the membrane glycoproteins encoded in the major histocompatibility gene complex. The products of the I region, the class II histocompatibility molecules (Ia molecules), are essential for accessory cells such as macrophages to present polypeptide antigens to helper T cells. This interaction, antigen presentation, is needed for T-cell recognition of the antigen and its consequent activation. How the Ia molecules regulate the immune response during antigen presentation is not known, although it is commonly thought to result from their association with the presented antigen. Recent studies, including the elucidation of the structure of the T-cell receptor, favour recognition of a single structure, an antigen-Ia complex. Here we report attempts to determine whether purified Ia glycoproteins have an affinity for polypeptide antigens presented by intact cells in an Ia-restricted manner. We first identified the epitope of a peptide antigen involved in presentation. Several laboratories have shown that globular proteins are altered (processed) in intracellular vesicles of the antigen-presenting cell before antigen presentation. A major component of the T-cell response is directed toward determinants found in the unfolded or denatured molecule, and our laboratory has shown that the determinant of the hen-egg lysozyme protein (HEL), presented in H-2k mice to T cells, is a sequence of only 10 amino acids. This portion resides in an area of the native molecule partially buried inside the molecule, in a beta-sheet conformation. To be presented, intact or native HEL must first be processed in acidic intracellular vesicles. Having isolated the peptide responsible for T-cell recognition of HEL, we sought a physical association of this peptide with purified, detergent-solubilized I-Ak molecules from B-hybridoma cells. We have found such an association, which may explain the role of the Ia glycoproteins in cellular interactions.

Specific and general HLA-DR binding motifs: comparison of algorithms

“…Also, the association pattern of peptides to different allele variants of murine Ia is a reflection of the MHC restriction of the immune response [3,4]. Several workers have attempted to unravel the relevant struc-tural requirements of TD h peptides to interact with murine [5][6][7] or human [8 -14] class II molecules.…”

Conformation of a T cell stimulating peptide in aqueous solution

“…The weight of evidence indicates that protein antigens are not recognised in their native three-dimensional conformations but are processed into short peptides [1] which bind directly to an MHC protein for presentation to the T cell receptor [2,3]. The X-ray structure of the human class I MHC protein, HLA-A2, reveals a probable peptide binding site formed by 2 antiparallel a~-helices and a region of/?-sheet [4,5].…”

Cellular Immune Recognition and the Biological Role of Major Transplantation Antigens

“…Obviously, what was unknown at the time was that MHC molecules or transplantation antigens are the antigen-presenting molecules that are recognized as a complex with the antigenic peptide. This became known in the subsequent 10 years, mostly thanks to the work of E. Unanue [61] and H. Grey and coworkers [62] mice there were two clonally specific T-cells that were specific for virus plus H-2 k and a second population that was specific for H-2 b . Therefore, T-cell receptors were either specific for the virally modified MHC molecule where neither details of either virus antigen nor MHC molecules were recognized in its original form (B) or T-cells were specific for a complex formed between MHC molecule and viral antigen, that the T-cell receptor recognized parts of the viral antigen and parts of the MHC molecule.…”