Can Trigger TCR Signaling T Cells Immobilized via the TCR Complex Cutting Edge: Mechanical Forces Acting on

Engagement of the TCR by antigenic peptides presented by the MHC activates specific T cells to control infections. Recent theoretical considerations have suggested that mechanical forces acting on the TCR may be important for receptor triggering. In this study, we directly tested the hypothesis that physical forces acting on the TCR can initiate signaling in T cells by mi-cromanipulation of individual T cells bound to artificial APCs expressing engineered TCR ligands. We find that mechanical forces acting on T cells bound to APCs via the TCR complex but not other surface receptors can initiate signaling in T cells in an Src kinase-dependent fashion. Our data indicate that T cells are mechanically sensitive when coupled to APCs by the TCR and indicates that the TCR may act as a mechanosensor. Our data provide new insight into TCR function. T he classical TCR is a heterodimer composed of a-and b-chains that are noncovalently associated on the plasma membrane of T cells with CD3, a complex composed of CD3«d heterodimers, CD3«g heterodimers, and CD3zz disulfide-linked homodimers. The TCR-a/b– chains do not contain signaling domains. Rather, engagement of peptides presented by the MHC (pMHC) by specific TCRs triggers the phosphorylation of tyrosine residues present in the ITAMs of the associated CD3 molecules, which then serve as docking sites for signaling molecules. These proximal events ultimately lead to activation of transcription factors (NF-kB, NFAT, and AP-1) that result in T cell proliferation , differentiation, and cytokine secretion. Extracellular mechanical forces can facilitate activation of surface receptors and regulate tyrosine phosphatase and kinase signaling (1). An important role for mechanical forces in TCR signaling has also been suggested. For example, actin-driven motility of T cells and shear forces were proposed to promote movement of TCRs into kinase-rich lipid rafts to facilitate TCR signaling (2). Forces that push or twist the TCR/CD3 complex upon ligand engagement have been conceptualized (3, 4). More recently, lateral and vertical forces acting on microclusters of TCR/pMHC complexes on lamellopodium have been suggested to be important for signal transduction (5), and a recent study provides evidence that the TCR can act as an anisotropic force sensor (6). Cytoskeletal forces induced during T cell detachment from APCs have been proposed to initiate TCR signaling (7). Mechanical forces have been suggested to expose CD3« and CD3z cytoplasmic domains for phosphorylation by Lck (8, 9). An important role for force-mediated changes in the TCR has …