Molecular design of the γδT cell receptor ectodomain encodes biologically fit ligand recognition in the absence of mechanosensing.

Autor:	Mallis RJ; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.; Department of Dermatology, Harvard Medical School, Boston, MA 02115.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Medicine, Harvard Medical School, Boston, MA 02115., Duke-Cohan JS; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Medicine, Harvard Medical School, Boston, MA 02115., Das DK; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235.; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37235., Akitsu A; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Medicine, Harvard Medical School, Boston, MA 02115., Luoma AM; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637., Banik D; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235.; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37235., Stephens HM; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235.; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37235., Tetteh PW; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Medicine, Harvard Medical School, Boston, MA 02115., Castro CD; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637., Krahnke S; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637., Hussey RE; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115., Lawney B; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115., Brazin KN; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Medicine, Harvard Medical School, Boston, MA 02115., Reche PA; Department of Immunology, Faculty of Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain., Hwang W; Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843; hwm@tamu.edu ejadams@uchicago.edu matt.lang@vanderbilt.edu ellis_reinherz@dfci.harvard.edu.; Department of Materials Science and Engineering, Texas A&M University, College Station, TX 77843.; Department of Physics and Astronomy, Texas A&M University, College Station, TX 77843.; School of Computational Sciences, Korea Institute for Advanced Study, 02455 Seoul, Korea., Adams EJ; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637; hwm@tamu.edu ejadams@uchicago.edu matt.lang@vanderbilt.edu ellis_reinherz@dfci.harvard.edu., Lang MJ; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235; hwm@tamu.edu ejadams@uchicago.edu matt.lang@vanderbilt.edu ellis_reinherz@dfci.harvard.edu.; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37235., Reinherz EL; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115; hwm@tamu.edu ejadams@uchicago.edu matt.lang@vanderbilt.edu ellis_reinherz@dfci.harvard.edu.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Medicine, Harvard Medical School, Boston, MA 02115.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Jun 29; Vol. 118 (26).
DOI:	10.1073/pnas.2023050118
Abstrakt:	High-acuity αβT cell receptor (TCR) recognition of peptides bound to major histocompatibility complex molecules (pMHCs) requires mechanosensing, a process whereby piconewton (pN) bioforces exert physical load on αβTCR-pMHC bonds to dynamically alter their lifetimes and foster digital sensitivity cellular signaling. While mechanotransduction is operative for both αβTCRs and pre-TCRs within the αβT lineage, its role in γδT cells is unknown. Here, we show that the human DP10.7 γδTCR specific for the sulfoglycolipid sulfatide bound to CD1d only sustains a significant load and undergoes force-induced structural transitions when the binding interface-distal γδ constant domain (C) module is replaced with that of αβ. The chimeric γδ-αβTCR also signals more robustly than does the wild-type (WT) γδTCR, as revealed by RNA-sequencing (RNA-seq) analysis of TCR-transduced Rag2 -/- thymocytes, consistent with structural, single-molecule, and molecular dynamics studies reflective of γδTCRs as mediating recognition via a more canonical immunoglobulin-like receptor interaction. Absence of robust, force-related catch bonds, as well as γδTCR structural transitions, implies that γδT cells do not use mechanosensing for ligand recognition. This distinction is consonant with the fact that their innate-type ligands, including markers of cellular stress, are expressed at a high copy number relative to the sparse pMHC ligands of αβT cells arrayed on activating target cells. We posit that mechanosensing emerged over ∼200 million years of vertebrate evolution to fulfill indispensable adaptive immune recognition requirements for pMHC in the αβT cell lineage that are unnecessary for the γδT cell lineage mechanism of non-pMHC ligand detection. Competing Interests: The authors declare no competing interest. (Copyright © 2021 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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