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Molecular characterization of HLA class II binding to the LAG-3 T cell co-inhibitory receptor.

ABSTRACT: Immune checkpoint inhibitors (antibodies that block the T cell co-inhibitory receptors PD-1/PD-L1 or CTLA-4) have revolutionized the treatment of some forms of cancer. Importantly, combination approaches using drugs that target both pathways have been shown to boost the efficacy of such treatments. Subsequently, several other T cell inhibitory receptors have been identified for the development of novel immune checkpoint inhibitors. Included in this list is the co-inhibitory receptor lymphocyte activation gene-3 (LAG-3), which is upregulated on T cells extracted from tumor sites that have suppressive or exhausted phenotypes. However, the molecular rules that govern the function of LAG-3 are still not understood. Using surface plasmon resonance combined with a novel bead-based assay (AlphaScreen^TM ), we demonstrate that LAG-3 can directly and specifically interact with intact human leukocyte antigen class II (HLA-II) heterodimers. Unlike the homologue CD4, which has an immeasurably weak affinity using these biophysical approaches, LAG-3 binds with low micromolar affinity. We further validated the interaction at the cell surface by staining LAG-3⁺ cells with pHLA-II-multimers. These data provide new insights into the mechanism by which LAG-3 initiates T cell inhibition.

SUBMITTER: MacLachlan BJ

PROVIDER: S-EPMC8101287 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Molecular characterization of HLA class II binding to the LAG-3 T cell co-inhibitory receptor.

MacLachlan Bruce J BJ Mason Georgina H GH Greenshields-Watson Alexander A Triebel Frederic F Gallimore Awen A Cole David K DK Godkin Andrew A

European journal of immunology 20201009 2

Immune checkpoint inhibitors (antibodies that block the T cell co-inhibitory receptors PD-1/PD-L1 or CTLA-4) have revolutionized the treatment of some forms of cancer. Importantly, combination approaches using drugs that target both pathways have been shown to boost the efficacy of such treatments. Subsequently, several other T cell inhibitory receptors have been identified for the development of novel immune checkpoint inhibitors. Included in this list is the co-inhibitory receptor lymphocyte a ...[more]

PMID: 32920841

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Project description:BackgroundMHC class II proteins bind oligopeptide fragments derived from proteolysis of pathogen antigens, presenting them at the cell surface for recognition by CD4+ T cells. Human MHC class II alleles are grouped into three loci: HLA-DP, HLA-DQ and HLA-DR. In contrast to HLA-DR and HLA-DQ, HLA-DP proteins have not been studied extensively, as they have been viewed as less important in immune responses than DRs and DQs. However, it is now known that HLA-DP alleles are associated with many autoimmune diseases. Quite recently, the X-ray structure of the HLA-DP2 molecule (DPA*0103, DPB1*0201) in complex with a self-peptide derived from the HLA-DR α-chain has been determined. In the present study, we applied a validated molecular docking protocol to a library of 247 modelled peptide-DP2 complexes, seeking to assess the contribution made by each of the 20 naturally occurred amino acids at each of the nine binding core peptide positions and the four flanking residues (two on both sides).ResultsThe free binding energies (FBEs) derived from the docking experiments were normalized on a position-dependent (npp) and on an overall basis (nap), and two docking score-based quantitative matrices (DS-QMs) were derived: QMnpp and QMnap. They reveal the amino acid preferences at each of the 13 positions considered in the study. Apart from the leading role of anchor positions p1 and p6, the binding to HLA-DP2 depends on the preferences at p2. No effect of the flanking residues was found on the peptide binding predictions to DP2, although all four of them show strong preferences for particular amino acids. The predictive ability of the DS-QMs was tested using a set of 457 known binders to HLA-DP2, originating from 24 proteins. The sensitivities of the predictions at five different thresholds (5%, 10%, 15%, 20% and 25%) were calculated and compared to the predictions made by the NetMHCII and IEDB servers. Analysis of the DS-QMs indicated an improvement in performance. Additionally, DS-QMs identified the binding cores of several known DP2 binders.ConclusionsThe molecular docking protocol, as applied to a combinatorial library of peptides, models the peptide-HLA-DP2 protein interaction effectively, generating reliable predictions in a quantitative assessment. The method is structure-based and does not require extensive experimental sequence-based data. Thus, it is universal and can be applied to model any peptide - protein interaction.

Dataset Information

Molecular characterization of HLA class II binding to the LAG-3 T cell co-inhibitory receptor.

Publications

Molecular characterization of HLA class II binding to the LAG-3 T cell co-inhibitory receptor.

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