Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function.

Nature Immunology
Frederike A HartlSusana Minguet

Abstract

Initiation of T cell antigen receptor (TCR) signaling involves phosphorylation of CD3 cytoplasmic tails by the tyrosine kinase Lck. How Lck is recruited to the TCR to initiate signaling is not well known. We report a previously unknown binding motif in the CD3ε cytoplasmic tail that interacts in a noncanonical mode with the Lck SH3 domain: the receptor kinase (RK) motif. The RK motif is accessible only upon TCR ligation, demonstrating how ligand binding leads to Lck recruitment. Binding of the Lck SH3 domain to the exposed RK motif resulted in local augmentation of Lck activity, CD3 phosphorylation, T cell activation and thymocyte development. Introducing the RK motif into a well-characterized 41BB-based chimeric antigen receptor enhanced its antitumor function in vitro and in vivo. Our findings underscore how a better understanding of the functioning of the TCR might promote rational improvement of chimeric antigen receptor design for the treatment of cancer.

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Citations

Jan 24, 2021·Nature Reviews. Cancer·Rebecca C Larson, Marcela V Maus
Oct 16, 2020·Cell Research·Bernard Malissen
Jan 26, 2021·Frontiers in Cell and Developmental Biology·Salma Pathan-ChhatbarWolfgang W Schamel
Oct 15, 2020·International Journal of Molecular Sciences·Nicholas J ChandlerMatthew E Call
Apr 2, 2021·Frontiers in Cell and Developmental Biology·Christopher E Rudd
Apr 10, 2021·Trends in Biotechnology·Rocío Castellanos-RuedaSai T Reddy
May 1, 2021·Cells·Frederike A HartlSusana Minguet
Jun 3, 2021·International Journal of Molecular Sciences·Omid Sascha YousefiWolfgang W A Schamel
Jun 26, 2021·Frontiers in Cell and Developmental Biology·Jatuporn NgoenkamSutatip Pongcharoen
Jul 30, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Paweł BorowiczAnne Spurkland
Aug 11, 2021·International Immunology·Keisuke Watanabe, Hiroyoshi Nishikawa
Sep 8, 2021·The Journal of Clinical Investigation·Hongxia DuanXiyun Yan
Oct 10, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Zeguang WuKatharine C Hsu

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Methods Mentioned

BETA
proximity ligation assay
Pull-down
NMR
nuclear magnetic resonance
Immunoprecipitation
flow cytometry
Transgenic
proximity ligation
transfection
ELISA

Software Mentioned

ImageQuantTL
BlobFinder
HADDOCK
MODELLER

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