title: Small organic compounds enhance antigen loading of class II major histocompatibility complex proteins by targeting the polymorphic P1 pocket.
abstract: Major histocompatibility complex (MHC) molecules are a key element of the cellular immune response. Encoded by the MHC they are a family of highly polymorphic peptide receptors presenting peptide antigens for the surveillance by T cells. We have shown that certain organic compounds can amplify immune responses by catalyzing the peptide loading of human class II MHC molecules HLA-DR. Here we show now that they achieve this by interacting with a defined binding site of the HLA-DR peptide receptor. Screening of a compound library revealed a set of adamantane derivatives that strongly accelerated the peptide loading rate. The effect was evident only for an allelic subset and strictly correlated with the presence of glycine at the dimorphic position beta86 of the HLA-DR molecule. The residue forms the floor of the conserved pocket P1, located in the peptide binding site of MHC molecule. Apparently, transient occupation of this pocket by the organic compound stabilizes the peptide-receptive conformation permitting rapid antigen loading. This interaction appeared restricted to the larger Gly(beta86) pocket and allowed striking enhancements of T cell responses for antigens presented by these "adamantyl-susceptible" MHC molecules. As catalysts of antigen loading, compounds targeting P1 may be useful molecular tools to amplify the immune response. The observation, however, that the ligand repertoire can be affected through polymorphic sites form the outside may also imply that environmental factors could induce allergic or autoimmune reactions in an allele-selective manner.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Strasse 10, D-13125 Berlin, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Höpner
authors.forename: Katharina
authors.initials: K
authors.lastname: Dickhaut
authors.forename: Maria
authors.initials: M
authors.lastname: Hofstätter
authors.forename: Heiko
authors.initials: H
authors.lastname: Krämer
authors.forename: Dominik
authors.initials: D
authors.lastname: Rückerl
authors.forename: J Arvid
authors.initials: JA
authors.lastname: Söderhäll
authors.forename: Shashank
authors.initials: S
authors.lastname: Gupta
authors.forename: Viviana
authors.initials: V
authors.lastname: Marin-Esteban
authors.forename: Ronald
authors.initials: R
authors.lastname: Kühne
authors.forename: Christian
authors.initials: C
authors.lastname: Freund
authors.forename: Günther
authors.initials: G
authors.lastname: Jung
authors.forename: Kirsten
authors.initials: K
authors.lastname: Falk
authors.forename: Olaf
authors.initials: O
authors.lastname: Rötzschke
mesh_terms: D000218:Adamantane / Q000494:pharmacology; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D017931:DNA Primers; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007313:Insecta; D008969:Molecular Sequence Data; D009930:Organic Chemicals / Q000494:pharmacology*; D011110:Polymorphism, Genetic
chemical_list: D017931:DNA Primers; D000949:Histocompatibility Antigens Class II; D009930:Organic Chemicals; D000218:Adamantane