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

MacLachlan, Bruce J., Mason, Georgina H., Greenshields Watson, Alexander, Triebel, Frederic, Gallimore, Awen ORCID:, Cole, David K. ORCID: and Godkin, Andrew ORCID: 2021. Molecular characterization of HLA class II binding to the LAG-3 T cell co-inhibitory receptor. European Journal of Immunology 51 (2) , pp. 331-341. 10.1002/eji.202048753

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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 (AlphaScreenTM), 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, LAG3 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

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Wiley
ISSN: 0014-2980
Funders: Wellcome Trust
Date of First Compliant Deposit: 14 May 2021
Date of Acceptance: 11 September 2020
Last Modified: 15 May 2024 01:09

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