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

Li, Ya-Chen; Chen, Bing‐Mae; Wu, Pei‐Chun; Cheng, Tian−Lu; Kao, Lung‐Sen; Tao, Mi‐Hua; Lieber, André; Roffler, Steve R.

doi:10.4049/jimmunol.0900775

Cited by 189 publications

(196 citation statements)

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“…This paradoxical extension of αβ TCR-pMHC-bond lifetime under force, so-called catch bond behavior, was then observed experimentally (19,33). The importance of force on TCR triggering has been confirmed in other work (34)(35)(36)(37)(38)(39)(40). However, during the initial T-cell surface contact, external (scanning) and internal (retrograde flow) force appear to operate in opposing directions (41).…”

mentioning

confidence: 69%

Mechanosensing drives acuity of αβ T-cell recognition

Feng

Brazin

Kobayashi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

156

197

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T lymphocytes use surface αβ T-cell receptors (TCRs) to recognize peptides bound to MHC molecules (pMHCs) on antigen-presenting cells (APCs). How the exquisite specificity of high-avidity T cells is achieved is unknown but essential, given the paucity of foreign pMHC ligands relative to the ubiquitous self-pMHC array on an APC. Using optical traps, we determine physicochemical triggering thresholds based on load and force direction. Strikingly, chemical thresholds in the absence of external load require orders of magnitude higher pMHC numbers than observed physiologically. In contrast, force applied in the shear direction (∼10 pN per TCR molecule) triggers T-cell Ca 2+ flux with as few as two pMHC molecules at the interacting surface interface with rapid positional relaxation associated with similarly directed motor-dependent transport via ∼8-nm steps, behaviors inconsistent with serial engagement during initial TCR triggering. These synergistic directional forces generated during cell motility are essential for adaptive T-cell immunity against infectious pathogens and cancers.mechanosensor | T-cell receptor | T-cell activation | optical tweezers | cellular force relaxation T he T-cell receptor (TCR) expressed on T lymphocytes of the adaptive immune system is a stout and squat (12-nm wide × 8-nm tall) multisubunit surface complex with a ligand binding moiety that is an αβ disulfide-linked heterodimer buttressed by the associated invariant CD3 subunits (1-3). The αβ chains are each encoded by V and J gene segments and in the case of the β, a D segment as well (4). The clone-specific TCR unique to each T lymphocyte endows mammals with the capacity to detect perturbations in host cellular function resulting from myriad infectious pathogens, physical damage (thermal, irradiation, etc.), or premalignant or malignant cellular transformations while averting strong self-reactivities that could induce autoimmunity (5).Signaling is initiated through ligation of the clonotype by its cognate antigenic peptide bound to an MHC molecule (pMHC) and displayed on the surface of antigen-presenting cells (APCs) (6, 7). Ligation impacts disposition and function of the associated CD3 dimers (CD3 γ, CD3 δ, and CD3ζζ) as well as the transmembrane domains of the TCR heterodimer and CD3 subunits that interdigitate in the membrane to signal into the cytoplasm (8, 9). A cascade of intracellular events involving phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) on the CD3 cytoplasmic domains with subsequent ZAP70 activation and downstream signaling follows (10, 11). Membrane-associated CD8 and CD4 coreceptors, marking cytotoxic T lymphocytes (CTLs) and helper T cells, respectively, function to bring the membrane-anchored Src family tyrosine kinase Lck to the TCR-pMHC complex for the initiation of ITAM phosphorylation. Signaling, in turn, leads to a transient rise of cytosolic Ca 2+ and other biochemical events resulting in transcriptional activation, ultimately resulting in developmental decisions or effector functi...

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mentioning

confidence: 69%

Mechanosensing drives acuity of αβ T-cell recognition

Feng

Brazin

Kobayashi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

156

197

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“…This is structurally plausible as the part of the TCRb chain is in close proximity to the relatively rigid CD3e ectodomain (Ghendler et al, 1998;Kim et al, 2010). More importantly, mechanical forces applied on the TCR heterodimer can trigger T cell signaling (Kim et al, 2009;Li et al, 2010;Husson et al, 2011). Additional evidence to support the necessity of actin-generated force for TCR triggering is the observation that monomeric agonist pMHC can trigger T cell signaling when anchored on the cell surface, but the same agonist in solution cannot.…”

Section: Journal Of Cell Sciencementioning

confidence: 84%

Modulation of T cell signaling by the actin cytoskeleton

Smoligovets

Groves

2013

Journal of Cell Science

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SummaryThe actin cytoskeleton provides a dynamic framework to support membrane organization and cellular signaling events. The importance of actin in T cell function has long been recognized to go well beyond the maintenance of cell morphology and transport of proteins. Over the past several years, our understanding of actin in T cell activation has expanded tremendously, in part owing to the development of methods and techniques to probe the complex interplay between actin and T cell signaling. On the one hand, biochemical methods have led to the identification of many key cytoskeleton regulators and new signaling pathways, whereas, on the other, the combination of advanced imaging techniques and physical characterization tools has allowed the spatiotemporal investigation of actin in T cell signaling. All those studies have made a profound impact on our understanding of the actin cytoskeleton in T cell activation. Many previous reviews have focused on the biochemical aspects of the actin cytoskeleton. However, here we will summarize recent studies from a biophysical perspective to explain the mechanistic role of actin in modulating T cell activation. We will discuss how actin modulates T cell activation on multiple time and length scales. Specifically, we will reveal the distinct roles of the actin filaments in facilitating TCR triggering, orchestrating 'signalosome' assembly and transport, and establishing protein spatial organization in the immunological synapse.

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“…A nonlinear response of the ␣␤TCR-pMHC bond was recently shown in biomembrane force probe and optical trap assays where single molecule interactions are probed (21,22). As a consequence of these and additional studies, the role of force in TCR-based signaling is becoming more readily appreciated (21)(22)(23)(24).…”

Section: And References Therein)mentioning

confidence: 93%

Pre-T Cell Receptors (Pre-TCRs) Leverage Vβ Complementarity Determining Regions (CDRs) and Hydrophobic Patch in Mechanosensing Thymic Self-ligands

Das

Mallis

Duke‐Cohan

et al. 2016

Journal of Biological Chemistry

104

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Edited by Peter CresswellThe pre-T cell receptor (pre-TCR) is a pT␣-␤ heterodimer functioning in early ␣␤ T cell development. Although once thought to be ligand-autonomous, recent studies show that preTCRs participate in thymic repertoire formation through recognition of peptides bound to major histocompatibility molecules (pMHC). Using optical tweezers, we probe pre-TCR bonding with pMHC at the single molecule level. Like the ␣␤TCR, the pre-TCR is a mechanosensor undergoing force-based structural transitions that dynamically enhance bond lifetimes and exploiting allosteric control regulated via the C␤ FG loop region. The pre-TCR structural transitions exhibit greater reversibility than TCR␣␤ and ordered force-bond lifetime curves. Higher piconewton force requires binding through both complementarity determining region loops and hydrophobic V␤ patch apposition. This patch functions in the pre-TCR as a surrogate V␣ domain, fostering ligand promiscuity to favor development of ␤ chains with self-reactivity but is occluded by ␣ subunit replacement of pT␣ upon ␣␤TCR formation. At the double negative 3 thymocyte stage where the pre-TCR is first expressed, pre-TCR interaction with self-pMHC ligands imparts growth and survival advantages as revealed in thymic stromal cultures, imprinting fundamental self-reactivity in the T cell repertoire. Collectively, our data imply the existence of sequential mechanosensor ␣␤TCR repertoire tuning via the pre-TCR.The mammalian adaptive immune system protects its host against infectious diseases as well as tumors in a highly specific manner. At the core of ␣␤ T lymphocyte recognition is self-versus non-self-discrimination, a functionality endowed by clonal cell-surface T cell receptors (TCRs) 4 (1-3). In the mammalian thymus, the millions of distinct TCRs expressed create a repertoire that is refined to eliminate unwanted autoreactive specificities prior to export into the peripheral lymphoid compartment (Ref. 4 and references therein).The earliest thymocytes, termed double negative (DN1-4), lack both CD4 and CD8 and expression of ␣␤TCR complexes (hereafter termed ␣␤TCRs) (5). Within the DN3 stage, a pre-TCR complex is generated comprised of a variable TCR␤ chain disulfide-linked to the invariant pT␣ subunit. In turn, the pT␣-␤ heterodimer is noncovalently complexed with the same CD3 dimers as found in the ␣␤TCR, namely CD3⑀␥, CD3⑀␦, and CD3 (1, 2). This pre-TCR complex triggers cellular survival and expansion and, importantly, induces expression of CD4 and CD8 co-receptors so that the thymocytes transit to the DP (CD4 ϩ CD8 ϩ ) thymocyte stage where rearrangement of the TCR␣ gene occurs. Only at the DP stage is the ␣␤TCR expressed. The pre-TCR signaling process, termed ␤ selection, also controls allelic exclusion of the TCR␤ locus in a given cell (6). Pre-TCR signaling components include tyrosine kinases Lck, Fyn, with Notch-1, Notch-1 ligand DL4, interleukin 7, and CXCR4 supporting pre-TCR function (5, 10). Although ␣␤TCR DP thymocyte selection processes involve pMHC-dependent posit...

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

Abstract: Material Supplementary 5.DC1http://www.jimmunol.org/content/suppl/2010/04/30/jimmunol.090077References

Cited by 189 publications

References 19 publications

Mechanosensing drives acuity of αβ T-cell recognition

Mechanosensing drives acuity of αβ T-cell recognition

Modulation of T cell signaling by the actin cytoskeleton

Pre-T Cell Receptors (Pre-TCRs) Leverage Vβ Complementarity Determining Regions (CDRs) and Hydrophobic Patch in Mechanosensing Thymic Self-ligands

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