The magnitude of LFA-1/ICAM-1 forces fine-tune TCR-triggered T cell activation

• Type of Material: Article
• Authors: Victor Pui-Yan Ma, Emory University; Yuesong Hu, Emory University; Anna Kellner, Emory University; Joshua M Brockman, Emory University; Arventh Velusamy, Emory University; Aaron T Blanchard, Emory University; Brian Evavold, Emory University; Ronen Alon, Weizmann Institute of Science; Khalid Salaita, Emory University
• Language: English
• Date: 2022-02-01
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.abg4485
• Title of Journal or Parent Work: SCIENCE ADVANCES
• Volume: 8
• Issue: 8
• Start Page: eabg4485
• End Page: eabg4485
• Grant/Funding Information: K.S. acknowledges financial support from NIH (R01GM124472 and R01GM131099). V.P.-Y.M., J.M.B., and A.T.B. are recipients of the National Cancer Institute Predoctoral to Postdoctoral Fellow Transition Award (K00CA223074 to V.P.-Y.M., K00CA234959 to J.M.B., and F99CA245789 to A.T.B.). A.V.K. is a recipient of Ruth L. Kirschstein Predoctoral Individual National Research Service Award (F31CA243502). B.D.E. is supported by NIH (R01AI147641).; R.A. is funded by the Israeli Science Foundation (791/17) and the Israel Cancer Research Fund (19-109-PG). This study was supported, in part, by the Emory Integrated Genomics Core (EIGC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the NIH.
• Keywords: ADHESION MOLECULE; INTEGRIN; Multidisciplinary Sciences; MECHANISMS; ANTIGEN RECEPTOR; LFA-1; MOLECULAR TENSION; ICAM-1; Science & Technology - Other Topics; ENGAGEMENT; Science & Technology; INTERMEDIATE; REVEALS
• Research Categories: Chemistry, General

Abstract

T cells defend against cancer and viral infections by rapidly scanning the surface of target cells seeking specific peptide antigens. This key process in adaptive immunity is sparked upon T cell receptor (TCR) binding of antigens within cell-cell junctions stabilized by integrin (LFA-1)/intercellular adhesion molecule–1 (ICAM-1) complexes. A long-standing question in this area is whether the forces transmitted through the LFA-1/ICAM-1 complex tune T cell signaling. Here, we use spectrally encoded DNA tension probes to reveal the first maps of LFA-1 and TCR forces generated by the T cell cytoskeleton upon antigen recognition. DNA probes that control the magnitude of LFA-1 force show that F>12 pN potentiates antigen-dependent T cell activation by enhancing T cell–substrate engagement. LFA-1/ICAM-1 mechanical events with F>12 pN also enhance the discriminatory power of the TCR when presented with near cognate antigens. Overall, our results show that T cells integrate multiple channels of mechanical information through different ligand-receptor pairs to tune function.