Ultrasmall silica nanoparticles directly ligate the T cell receptor complex.
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Kinrade, Stephen D
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences
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Vis, B., Hewitt, R., Monie, T., Fairbairn, C., Turner, S., Kinrade, S. D., & Powell, J. (2020). Ultrasmall silica nanoparticles directly ligate the T cell receptor complex.. Proceedings of the National Academy of Sciences of the United States of America, 117 (1), 285-291. https://doi.org/10.1073/pnas.1911360117
The impact of ultrasmall nanoparticles (< 10 nm diameter) on the immune system is poorly understood. Recently, ultrasmall silica nanoparticles (USSN), which have gained increasing attention for therapeutic applications, were shown to stimulate T lymphocytes directly and at relatively low exposure doses. Delineating underlying mechanisms and associated cell signalling will hasten therapeutic translation and is reported herein. Using competitive binding assays and molecular modelling, we established that the TCR:CD3 complex is required for USSN-induced T cell activation, and that direct receptor complex-particle interactions are permitted both sterically and electrostatically. Activation is not limited to αβ TCR-bearing T cells since those with γδ TCR showed similar responses, implying that USSN mediate their effect by binding to extracellular domains of the flanking CD3 regions of the TCR complex. We confirmed that USSN initiated the signalling pathway immediately downstream of the TCR with rapid phosphorylation of both zeta-chain-associated protein 70 (Zap70) and linker for activation of T cells (LAT) protein. T cell proliferation or IL-2 secretion were only triggered by USSN when costimulatory anti-CD28 or phorbate esters were present, however, demonstrating that the specific impact of USSN is in initiation of the primary, NFAT-pathway signalling from the TCR complex. Hence, we have established that USSN are partial agonists for the TCR complex owing to induction of the primary T cell activation signal. Their ability to bind the TCR complex rapidly, and then to dissolve into benign orthosilicic acid, makes them an appealing option for therapies targeted at transient TCR:CD3 receptor binding.
T-Lymphocytes, Humans, Silicon Dioxide, Receptor-CD3 Complex, Antigen, T-Cell, Interleukin-2, Lymphocyte Activation, Signal Transduction, Cell Proliferation, Phosphorylation, Models, Molecular, Nanoparticles, CD3 Complex, CD28 Antigens
These studies were supported by grants from the UK Medical Research Council (Grant number MR/R005699/1) and the Natural Sciences and Engineering Research Council of Canada, as well as through sponsorship from HS Pharmaceuticals LLC.
External DOI: https://doi.org/10.1073/pnas.1911360117
This record's URL: https://www.repository.cam.ac.uk/handle/1810/300665
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