@article{a9e052c8bb0c410296fafa8b3a2c084c,
title = "LAG3 associates with TCR–CD3 complexes and suppresses signaling by driving co-receptor–Lck dissociation",
abstract = "LAG3 is an inhibitory receptor that is highly expressed on exhausted T cells. Although LAG3-targeting immunotherapeutics are currently in clinical trials, how LAG3 inhibits T cell function remains unclear. Here, we show that LAG3 moved to the immunological synapse and associated with the T cell receptor (TCR)-CD3 complex in CD4+ and CD8+ T cells, in the absence of binding to major histocompatibility complex class II—its canonical ligand. Mechanistically, a phylogenetically conserved, acidic, tandem glutamic acid–proline repeat in the LAG3 cytoplasmic tail lowered the pH at the immune synapse and caused dissociation of the tyrosine kinase Lck from the CD4 or CD8 co-receptor, which resulted in a loss of co-receptor–TCR signaling and limited T cell activation. These observations indicated that LAG3 functioned as a signal disruptor in a major histocompatibility complex class II-independent manner, and provide insight into the mechanism of action of LAG3-targeting immunotherapies.",
author = "Clifford Guy and Mitrea, {Diana M.} and Chou, {Po Chien} and Jamshid Temirov and Vignali, {Kate M.} and Xueyan Liu and Hui Zhang and Richard Kriwacki and Bruchez, {Marcel P.} and Watkins, {Simon C.} and Workman, {Creg J.} and Vignali, {Dario A.A.}",
note = "Funding Information: We wish to thank everyone in the Vignali laboratory (Vignali-lab.com ; @Vignali_Lab) for all their constructive comments and advice during this project. The authors would like to thank G. Lennon, R. Cross and P. Ingle of the St. Jude Immunology Flow Lab for cell sorting and valuable assistance; A. Yates, D. Falkner and H. Shen from the Immunology Flow Core at the University of Pittsburgh for cell sorting; A. McKenna and K. Forbes for maintenance, breeding and genotyping of mouse colonies at St. Jude Children{\textquoteright}s Research Hospital; E. Brunazzi for maintenance, breeding and genotyping of mouse colonies at the University of Pittsburgh; and the staffs of the Shared Animal Resource Center and the Division of Laboratory Animal Services for the animal husbandry A. Philips for assistance with NMR data analysis. Images were acquired, in part, at the Cell and Tissue Imaging Center, and peptide synthesis was performed by the Hartwell Center for Macromolecular Synthesis, which are supported by SJCRH and NCI P30 CA021765. This work was supported by the National Institutes of Health (P01 AI108545, R01 AI129893 to D.A.A.V.; R01 AI144422 to D.A.A.V and C.J.W.), NCI Comprehensive Cancer Center Support CORE grant (CA047904, to D.A.A.V. and R.K.), and ALSAC (to D.A.A.V. and R.K.). Funding Information: We wish to thank everyone in the Vignali laboratory ( Vignali-lab.com ; @Vignali_Lab ) for all their constructive comments and advice during this project. The authors would like to thank G. Lennon, R. Cross and P. Ingle of the St. Jude Immunology Flow Lab for cell sorting and valuable assistance; A. Yates, D. Falkner and H. Shen from the Immunology Flow Core at the University of Pittsburgh for cell sorting; A. McKenna and K. Forbes for maintenance, breeding and genotyping of mouse colonies at St. Jude Children{\textquoteright}s Research Hospital; E. Brunazzi for maintenance, breeding and genotyping of mouse colonies at the University of Pittsburgh; and the staffs of the Shared Animal Resource Center and the Division of Laboratory Animal Services for the animal husbandry A. Philips for assistance with NMR data analysis. Images were acquired, in part, at the Cell and Tissue Imaging Center, and peptide synthesis was performed by the Hartwell Center for Macromolecular Synthesis, which are supported by SJCRH and NCI P30 CA021765. This work was supported by the National Institutes of Health (P01 AI108545, R01 AI129893 to D.A.A.V.; R01 AI144422 to D.A.A.V and C.J.W.), NCI Comprehensive Cancer Center Support CORE grant (CA047904, to D.A.A.V. and R.K.), and ALSAC (to D.A.A.V. and R.K.). Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = may,
doi = "10.1038/s41590-022-01176-4",
language = "English (US)",
volume = "23",
pages = "757--767",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "5",
}