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

Title data

Hartl, Frederike A. ; Beck-García, Esmeralda ; Woessner, Nadine M. ; Flachsmann, Lea J. ; Velasco Cárdenas, Rubí M.-H. ; Brandl, Simon M. ; Taromi, Sanaz ; Fiala, Gina J. ; Morath, Anna ; Mishra, Pankaj ; Yousefi, O. Sascha ; Zimmermann, Julia ; Hoefflin, Nico ; Köhn, Maja ; Wöhrl, Birgitta M. ; Zeiser, Robert ; Schweimer, Kristian ; Günther, Stefan ; Schamel, Wolfgang W. ; Minguet, Susana:
Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function.
In: Nature Immunology. (July 2020) .
ISSN 1529-2916
DOI: https://doi.org/10.1038/s41590-020-0732-3

Abstract in another language

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.

Further data

Item Type: Article in a journal
Refereed: Yes
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biopolymers
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biopolymers > Chair Biopolymers - Apl. Prof. Dr. Birgitta Wöhrl
Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Result of work at the UBT: Yes
DDC Subjects: 500 Science > 540 Chemistry
500 Science > 570 Life sciences, biology
Date Deposited: 22 Jul 2020 08:59
Last Modified: 28 Jul 2020 13:21
URI: https://eref.uni-bayreuth.de/id/eprint/56027