The structure of a T-cell mechanosensor

Reinherz, Ellis L.

doi:10.1038/d41586-019-02646-w

Cited by 15 publications

(17 citation statements)

References 13 publications

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“…Previous structural data also suggested that a complete signaling complex in solution may be dimeric (211). It is thought that the antigen-bound TCR then interacts with actin and other signals to function as a mechanosensory unit (123,218).…”

Section: Spatial and Geometric Constraints Within The Ismentioning

confidence: 99%

Considerations of Antibody Geometric Constraints on NK Cell Antibody Dependent Cellular Cytotoxicity

Murin

2020

Front. Immunol.

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It has been well-established that antibody isotype, glycosylation, and epitope all play roles in the process of antibody dependent cellular cytotoxicity (ADCC). For natural killer (NK) cells, these phenotypes are linked to cellular activation through interaction with the IgG receptor FcγRIIIa, a single pass transmembrane receptor that participates in cytoplasmic signaling complexes. Therefore, it has been hypothesized that there may be underlying spatial and geometric principles that guide proper assembly of an activation complex within the NK cell immune synapse. Further, synergy of antibody phenotypic properties as well as allosteric changes upon antigen binding may also play an as-of-yet unknown role in ADCC. Understanding these facets, however, remains hampered by difficulties associated with studying immune synapse dynamics using classical approaches. In this review, I will discuss relevant NK cell biology related to ADCC, including the structural biology of Fc gamma receptors, and how the dynamics of the NK cell immune synapse are being studied using innovative microscopy techniques. I will provide examples from the literature demonstrating the effects of spatial and geometric constraints on the T cell receptor complex and how this relates to intracellular signaling and the molecular nature of lymphocyte activation complexes, including those of NK cells. Finally, I will examine how the integration of high-throughput and "omics" technologies will influence basic NK cell biology research moving forward. Overall, the goal of this review is to lay a basis for understanding the development of drugs and therapeutic antibodies aimed at augmenting appropriate NK cell ADCC activity in patients being treated for a wide range of illnesses.

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Section: Spatial and Geometric Constraints Within The Ismentioning

confidence: 99%

Considerations of Antibody Geometric Constraints on NK Cell Antibody Dependent Cellular Cytotoxicity

Murin

2020

Front. Immunol.

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“…During cell adhesion and migration immune cells are exposed to various biophysical stimuli including shear (in the circulation as well as during cell adhesion), deformation (when squeezing though narrow capillary passages or in transmigration), or cyclic mechanical stretch (in lung and heart as a result of ventilation or cardiac function). Although mechanical forces have been shown to impact signaling during adaptive immune processes (11)(12)(13), their effects on innate immunity are rarely considered and remain poorly understood. Recent studies, however, have implicated TRPV4 function in the regulation of innate immune responses (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

TRPV4—A Missing Link Between Mechanosensation and Immunity

Michalick

Kuebler

2020

Front. Immunol.

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“…contact with both the CD3 γ and CD3 δ EC domains in the assembled TCR -CD3 complex (see Figure 1). Outstanding questions concern the orientational variability of the TCRαβ EC domain relative to the membrane, in which the TCR -CD3 complex complex is embedded in its native environment, and the structural variability of the overall TCR -CD3 complex, which is constrained by the chemical crosslinking of the protein chains in the approach of Dong et al (Dong et al, 2019;Reinherz, 2019). The Cβ FG loop, for example, has been suggested to play a key role in T cell activation (Kim et al, 2010;Touma et al, 2006), but exhibits only rather limited contacts with CD3 γ in the cryo-EM structure (see Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Structural variability and concerted motions of the T cell receptor – CD3 complex

Pandey

Różycki

Lipowsky

et al. 2021

Preprint

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We investigate the structural and orientational variability of the membrane-embedded T cell receptor (TCR) - CD3 complex in extensive atomistic molecular dynamics simulations based on the recent cryo-EM structure determined by Dong et al., Nature 573:546 (2019). We find that the TCR extracellular (EC) domain is highly variable in its orientation by attaining tilt angles relative to the membrane normal that range from 15° to 55°. The tilt angle of the TCR EC domain is both coupled to a rotation of the domain and to characteristic changes throughout the TCR - CD3 complex, in particular in the EC interactions of the Cβ FG loop of the TCR, as well as in the orientation of transmembrane helices. The concerted motions of the membrane-embedded TCR - CD3 complex revealed in our simulations provide atomistic insights for force-based models of TCR activation, which involve such structural changes in response to tilt-inducing forces on antigen-bound TCRs.

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The structure of a T-cell mechanosensor

Cited by 15 publications

References 13 publications

Considerations of Antibody Geometric Constraints on NK Cell Antibody Dependent Cellular Cytotoxicity

Considerations of Antibody Geometric Constraints on NK Cell Antibody Dependent Cellular Cytotoxicity

TRPV4—A Missing Link Between Mechanosensation and Immunity

Structural variability and concerted motions of the T cell receptor – CD3 complex

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