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 ␤86 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 ␤86 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.

Class II MHC/Peptide Interaction in Leishmania donovani Infection: Implications in Vaccine Design

“…It is known that Ada enhances loading of peptide to MHC-II (41). The Ada-treated I-MFs showed ∼7-fold increased T cell stimulation compared with I-MFs.…”

“…The treatment of infected MFs was carried out as described (41). Briefly, infected MFs were treated with 2-(1-adamantyl)-ethanol (Ada; 500 mM) for 4 h in the presence of 5 mM OVA 323-339 peptide.…”

On Peptides and Altered Peptide Ligands: From Origin, Mode of Action and Design to Clinical Application (Immunotherapy)

“…In the past, several groups of small molecules catalyzing peptide exchange in a DM-independent manner, and thus acting as ‘MHC loading enhancers' (MLE), have been identified. This collection includes simple alcohols [118], short linear peptides of 2-7 amino acids in length [119], circular peptides [120], adamantyl compounds [121], inorganic metal complexes and other small-molecule enhancers [122]. What are the mechanistic principles of these substances?…”

Molecular and structural determinants of adamantyl susceptibility to HLA-DRs allelic variants: an in silico approach to understand the mechanism of MLEs

“…However, for the activation of MHC II molecules, the conformation itself plays a major role to initiate the whole process of tumor cell killing. Various methods are used to stimulate the peptide-receptive state of MHC II protein by MHC Loading Enhancers (MLEs), small organic catalytic compounds that are simply added to the antigen mixture [16][17][18][19][20][21] but all these methods are under consideration due to the stimulation of autoimmune responses [22]. It is safer to use the naturally occurring MHC II molecules by making them more responsive rather than entangling ourselves with the approach of generating large recombinant fusion proteins.…”

“…cells evading intracellular processing can lead to broaden the spectrum of antigens able to be presented by DCs, coherent with their role as protector in the immune system [25,26]. Small organic compounds (MLEs) can improve antigen loading by switching the MHC II protein from the inactive peptide non-receptive state to the active peptide-receptive state and by triggering the release of ligands with lower affinity [17,19]. Similarly to HLA-DM, these MLEs stabilize a peptide receptive state followed by accelerated antigenloading and ligand exchange.…”