Mechanotransduction in T Cell Development, Differentiation and Function

Rushdi, Muaz Nik; Li, Kaitao; Yuan, Zhou; Travaglino, Stefano; Grakoui, Arash; Zhu, Cheng

doi:10.3390/cells9020364

Cited by 23 publications

(18 citation statements)

References 144 publications

(244 reference statements)

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“…The coupling of the tilt angle of the TCRαβ EC domain to overall conformational changes in the TCR -CD3 complex, which we observe in our MD simulations, is of relevance for TCR signaling mechanisms that are based on transversal, tilt-inducing forces. Transversal forces acting on the TCRαβ EC domain after binding to MHC-peptide-antigen complexes arise during the scanning of antigen-presenting cells by T cells (Göhring et al, 2020;Cai et al, 2017;Huse, 2017;Rushdi et al, 2020). While experiments show that the TCR -CD3 complex responds to mechanical force (Kim et al, 2009;Feng et al, 2017) and that the Cβ FG loop plays a key role in this response (Das et al, 2015), an outstanding question is how this force alters the conformation of the TCR -CD3 complex (Courtney et al, 2018).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

Pandey

Różycki

Lipowsky

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The coupling of the tilt angle of the TCRαβ EC domain to overall conformational changes in the TCR -CD3 complex, which we observe in our MD simulations, provides insights on conformational changes induced by transversal, tilt-inducing forces. Transversal forces acting on the TCRαβ EC domain after binding to MHC-peptide-antigen complexes arise during the scanning of antigenpresenting cells by T cells (Göhring et al, 2020;Cai et al, 2017;Huse, 2017;Rushdi et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

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

Pandey

Różycki

Lipowsky

et al. 2021

eLife

View full text Add to dashboard Cite

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. (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 C_ 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 on conformational changes of the complex in response to tilt-inducing forces on antigen-bound TCRs.

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“…Mechanical forces, either on a molecular or cellular level, are known to have an impact on the immune system (Huse 2017). T cells, in particular, are considered sensitive mechanosensors since mechanical forces influence many of their functions (Rushdi et al 2020). T cells also serve as a mechanicalimmunological bridge in the oral mucosa, a tissue frequently challenged by mechanical forces.…”

Section: Introductionmentioning

confidence: 99%

γδT Cells Are Essential for Orthodontic Tooth Movement

et al. 2021

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Sustained mechanical forces applied to tissue are known to shape local immunity. In the oral mucosa, mechanical stress, either naturally induced by masticatory forces or externally via mechanical loading during orthodontic tooth movement (OTM), is translated, in part, by T cells to alveolar bone resorption. Nevertheless, despite being considered critical for OTM, depletion of CD4+ and CD8+ T cells is reported to have no impact on tooth movement, thus questioning the function of αβT cells in OTM-associated bone resorption. To further address the role of T cells in OTM, we first characterized the leukocytes residing in the periodontal ligament (PDL), the tissue of interest during OTM, and compared it to the neighboring gingiva. Unlike the gingiva, monocytes and neutrophils represent the major leukocytes of the PDL. These myeloid cells were also the main leukocytes in the PDL of germ-free mice, although at lower levels than SPF mice. T lymphocytes were more enriched in the gingiva than the PDL, yet in both tissues, the relative fraction of the γδT cells was higher than the αβ T cells. We thus sought to examine the role of γδT cells in OTM. γδT cells residing in the PDL were mainly Vγ6+ and produced interleukin (IL)–17A but not interferon-γ. Using Tcrd-GDL mice allowing conditional ablation of γδT cells in vivo, we demonstrate that OTM was greatly diminished in the absence of γδT cells. Further analysis revealed that ablation of γδT cells decreased early IL-17A expression, monocyte and neutrophil recruitment, and the expression of the osteoclastogenic molecule receptor activator of nuclear factor–κβ ligand. This, eventually, resulted in reduced numbers of osteoclasts in the pressure site during OTM. Collectively, our data suggest that γδT cells are essential in OTM for translating orthodontic mechanical forces to bone resorption, required for relocating the tooth in the alveolar bone.

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Mechanotransduction in T Cell Development, Differentiation and Function

Cited by 23 publications

References 144 publications

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

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

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

γδT Cells Are Essential for Orthodontic Tooth Movement

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