A TCR mechanotransduction signaling loop induces negative selection in the thymus

• Type of Material: Article
• Authors: Jinsung Hong, Georgia Institute of Technology; Chenghao Ge, Georgia Institute of Technology; Prithiviraj Jothikumar, Georgia Institute of Technology; Zhou Yuan, Georgia Institute of Technology; Baoyu Liu, Georgia Institute of Technology; Ke Bai, Georgia Institute of Technology; Kaitao Li, Georgia Institute of Technology; William Rittase, Georgia Institute of Technology; Miho Shinzawa, National Institutes of Health; Yun Zhang, Emory University; Amy Palin, National Institutes of Health; Paul Love, National Institutes of Health; Xinhua Yu, University of Memphis; Khalid Salaita, Emory University; Brian Evavold, Emory University; Alfred Singer, National Institutes of Health; Cheng Zhu, Emory University
• Language: English
• Date: 2018-12-01
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41590-018-0259-z
• Title of Journal or Parent Work: Nature Immunology
• ISSN: 1529-2908
• Volume: 19
• Issue: 12
• Start Page: 1379
• End Page: +
• Grant/Funding Information: This work was supported by NIH grants CA214354 and AI124680 (to C.Z.); and NS071518 and AI096879 (to B.E.).
• Keywords: CD8/P56(LCK); Life Sciences & Biomedicine; AFFINITY; CD4(+)CD8(+) THYMOCYTES; CATCH BONDS; CD8; BINDING; LIGAND; Immunology; Science & Technology; RECRUITMENT; KINETICS; T-CELL-RECEPTOR
• Research Categories: Engineering, Biomedical; Health Sciences, Immunology

Abstract

The T cell antigen receptor (TCR) expressed on thymocytes interacts with self-peptide major histocompatibility complex (pMHC) ligands to signal apoptosis or survival. Here, we found that negative-selection ligands induced thymocytes to exert forces on the TCR and the co-receptor CD8 and formed cooperative TCR–pMHC–CD8 trimolecular ‘catch bonds’, whereas positive-selection ligands induced less sustained thymocyte forces on TCR and CD8 and formed shorter-lived, independent TCR–pMHC and pMHC–CD8 bimolecular ‘slip bonds’. Catch bonds were not intrinsic to either the TCR–pMHC or the pMHC–CD8 arm of the trans (cross-junctional) heterodimer but resulted from coupling of the extracellular pMHC–CD8 interaction to the intracellular interaction of CD8 with TCR–CD3 via associated kinases to form a cis (lateral) heterodimer capable of inside-out signaling. We suggest that the coupled trans–cis heterodimeric interactions form a mechanotransduction loop that reinforces negative-selection signaling that is distinct from positive-selection signaling in the thymus.