A TCR Mechanotransduction Signaling Loop Induces Negative Selection in the Thymus

Overview

Journal Nat Immunol

Date 2018 Nov 14

PMID 30420628

Citations 78

Authors

Jinsung Hong

Chenghao Ge

Prithiviraj Jothikumar

Zhou Yuan

Baoyu Liu

Ke Bai

Kaitao Li

William Rittase

Miho Shinzawa

Yun Zhang

Amy Palin

Paul Love

Xinhua Yu

Khalid Salaita

Brian D Evavold

Alfred Singer

Cheng Zhu

Affiliations

Soon will be listed here.

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.

Citing Articles

TCR catch bonds nonlinearly control CD8 cooperation to shape T cell specificity.

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Mechanical force regulates ligand binding and function of PD-1.

Li K, Cardenas-Lizana P, Lyu J, Kellner A, Li M, Cong P Nat Commun. 2024; 15(1):8339.

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