Ligand-engaged TCR is triggered by Lck not associated with CD8 coreceptor

The earliest molecular events in T-cell recognition have not yet been fully described, and the initial T-cell receptor (TCR)-triggering mechanism remains a subject of controversy. Here, using total internal reflection/Forster resonance energy transfer microscopy, we observe a two-stage interaction b...

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Published inNature communications Vol. 5; no. 1; p. 5624
Main Authors Casas, Javier, Brzostek, Joanna, Zarnitsyna, Veronika I., Hong, Jin-sung, Wei, Qianru, Hoerter, John A. H., Fu, Guo, Ampudia, Jeanette, Zamoyska, Rose, Zhu, Cheng, Gascoigne, Nicholas R. J.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 27.11.2014
Nature Publishing Group
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ISSN2041-1723
2041-1723
DOI10.1038/ncomms6624

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Abstract The earliest molecular events in T-cell recognition have not yet been fully described, and the initial T-cell receptor (TCR)-triggering mechanism remains a subject of controversy. Here, using total internal reflection/Forster resonance energy transfer microscopy, we observe a two-stage interaction between TCR, CD8 and major histocompatibility complex (MHC)-peptide. There is an early (within seconds) interaction between CD3ζ and the coreceptor CD8 that is independent of the binding of CD8 to MHC, but that requires CD8 association with Lck. Later (several minutes) CD3ζ–CD8 interactions require CD8–MHC binding. Lck can be found free or bound to the coreceptor. This work indicates that the initial TCR-triggering event is induced by free Lck. The early signalling events that trigger initial T-cell receptor signalling are not clearly defined. Here the authors show that this occurs in two stages, the first between the CD8 coreceptor and CD3 requiring Lck association to CD8, while the second interaction requires binding of major histocompatibility molecules.
AbstractList The earliest molecular events in T-cell recognition have not yet been fully described, and the initial T-cell receptor (TCR)-triggering mechanism remains a subject of controversy. Here, using total internal reflection/Forster resonance energy transfer microscopy, we observe a two-stage interaction between TCR, CD8 and major histocompatibility complex (MHC)-peptide. There is an early (within seconds) interaction between CD3ζ and the coreceptor CD8 that is independent of the binding of CD8 to MHC, but that requires CD8 association with Lck. Later (several minutes) CD3ζ-CD8 interactions require CD8-MHC binding. Lck can be found free or bound to the coreceptor. This work indicates that the initial TCR-triggering event is induced by free Lck.
The earliest molecular events in T-cell recognition have not yet been fully described, and the initial T-cell receptor (TCR)-triggering mechanism remains a subject of controversy. Here, using total internal reflection/Forster resonance energy transfer microscopy, we observe a two-stage interaction between TCR, CD8 and major histocompatibility complex (MHC)-peptide. There is an early (within seconds) interaction between CD3ζ and the coreceptor CD8 that is independent of the binding of CD8 to MHC, but that requires CD8 association with Lck. Later (several minutes) CD3ζ–CD8 interactions require CD8–MHC binding. Lck can be found free or bound to the coreceptor. This work indicates that the initial TCR-triggering event is induced by free Lck. The early signalling events that trigger initial T-cell receptor signalling are not clearly defined. Here the authors show that this occurs in two stages, the first between the CD8 coreceptor and CD3 requiring Lck association to CD8, while the second interaction requires binding of major histocompatibility molecules.
The earliest molecular events in T-cell recognition have not yet been fully described, and the initial T-cell receptor (TCR)-triggering mechanism remains a subject of controversy. Here, using total internal reflection/Forster resonance energy transfer microscopy, we observe a two-stage interaction between TCR, CD8 and major histocompatibility complex (MHC)-peptide. There is an early (within seconds) interaction between CD3ζ and the coreceptor CD8 that is independent of the binding of CD8 to MHC, but that requires CD8 association with Lck. Later (several minutes) CD3ζ-CD8 interactions require CD8-MHC binding. Lck can be found free or bound to the coreceptor. This work indicates that the initial TCR-triggering event is induced by free Lck.The earliest molecular events in T-cell recognition have not yet been fully described, and the initial T-cell receptor (TCR)-triggering mechanism remains a subject of controversy. Here, using total internal reflection/Forster resonance energy transfer microscopy, we observe a two-stage interaction between TCR, CD8 and major histocompatibility complex (MHC)-peptide. There is an early (within seconds) interaction between CD3ζ and the coreceptor CD8 that is independent of the binding of CD8 to MHC, but that requires CD8 association with Lck. Later (several minutes) CD3ζ-CD8 interactions require CD8-MHC binding. Lck can be found free or bound to the coreceptor. This work indicates that the initial TCR-triggering event is induced by free Lck.
The earliest molecular events in T cell recognition have not yet been fully described, and the initial T cell receptor (TCR) triggering mechanism remains a subject of controversy. Here, using TIRF/FRET microscopy, we observe a two-stage interaction between TCR, CD8, and MHCp. There is an early (within seconds) interaction between CD3ζ and the coreceptor CD8 that is independent of the binding of CD8 to MHC, but that requires CD8 association with Lck. Later (several minutes) CD3ζ-CD8 interactions require CD8-MHC binding. Lck can be found free or bound to the coreceptor. This work indicates that the initial TCR triggering event is induced by free Lck.
ArticleNumber 5624
Author Gascoigne, Nicholas R. J.
Zarnitsyna, Veronika I.
Zamoyska, Rose
Brzostek, Joanna
Hoerter, John A. H.
Fu, Guo
Zhu, Cheng
Casas, Javier
Wei, Qianru
Hong, Jin-sung
Ampudia, Jeanette
AuthorAffiliation 1 Department of Microbiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 5 Science Drive 2, Singapore 117545
2 Department of Immunology and Microbial Sciences, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA, 92037 USA
3 Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
4 George W Woodruff School of Mechanical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
5 Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, Scotland, UK
AuthorAffiliation_xml – name: 1 Department of Microbiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 5 Science Drive 2, Singapore 117545
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– name: 2 Department of Immunology and Microbial Sciences, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA, 92037 USA
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  surname: Casas
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/25427562$$D View this record in MEDLINE/PubMed
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Present addresses: V.I.Z., Department of Biology, Emory University, Atlanta, GA; J.A.H.H., Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA; G.F., State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Fujian 361102, China; J.A., Takeda Pharmaceutical Company, San Diego, CA 92121, USA.
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Snippet The earliest molecular events in T-cell recognition have not yet been fully described, and the initial T-cell receptor (TCR)-triggering mechanism remains a...
The earliest molecular events in T cell recognition have not yet been fully described, and the initial T cell receptor (TCR) triggering mechanism remains a...
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Animals
CD3 Complex - genetics
CD3 Complex - metabolism
CD8 Antigens - genetics
CD8 Antigens - metabolism
Energy transfer
Female
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humanities and Social Sciences
Ligands
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - genetics
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism
Major Histocompatibility Complex
Male
Mice
Mice, Knockout
multidisciplinary
Protein Binding
Receptors, Antigen, T-Cell - genetics
Receptors, Antigen, T-Cell - metabolism
Science
Science (multidisciplinary)
Synapses - enzymology
Synapses - genetics
Synapses - metabolism
T-Lymphocytes - metabolism
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Title Ligand-engaged TCR is triggered by Lck not associated with CD8 coreceptor
URI https://link.springer.com/article/10.1038/ncomms6624
https://www.ncbi.nlm.nih.gov/pubmed/25427562
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https://pubmed.ncbi.nlm.nih.gov/PMC4248239
Volume 5
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