Small organic compounds enhance antigen loading of class II major histocompatibility complex proteins by targeting the polymorphic P1 pocket.
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.
Höpner
Sabine
S
Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Strasse 10, D-13125 Berlin, Germany.
Dickhaut
Katharina
K
Hofstätter
Maria
M
Krämer
Heiko
H
Rückerl
Dominik
D
Söderhäll
J Arvid
JA
Gupta
Shashank
S
Marin-Esteban
Viviana
V
Kühne
Ronald
R
Freund
Christian
C
Jung
Günther
G
Falk
Kirsten
K
Rötzschke
Olaf
O
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
D017931:DNA Primers; D000949:Histocompatibility Antigens Class II; D009930:Organic Chemicals; D000218:Adamantane