Cargando…

Nanoscale Colocalization of NK Cell Activating and Inhibitory Receptors Controls Signal Integration

Natural killer (NK) cell responses depend on the balance of signals from inhibitory and activating receptors. However, how the integration of antagonistic signals occurs upon NK cell–target cell interaction is not fully understood. Here we provide evidence that NK cell inhibition via the inhibitory...

Descripción completa

Detalles Bibliográficos
Autores principales: Tomaz, David, Pereira, Pedro Matos, Guerra, Nadia, Dyson, Julian, Gould, Keith, Henriques, Ricardo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9198454/
https://www.ncbi.nlm.nih.gov/pubmed/35720315
http://dx.doi.org/10.3389/fimmu.2022.868496
_version_ 1784727621131567104
author Tomaz, David
Pereira, Pedro Matos
Guerra, Nadia
Dyson, Julian
Gould, Keith
Henriques, Ricardo
author_facet Tomaz, David
Pereira, Pedro Matos
Guerra, Nadia
Dyson, Julian
Gould, Keith
Henriques, Ricardo
author_sort Tomaz, David
collection PubMed
description Natural killer (NK) cell responses depend on the balance of signals from inhibitory and activating receptors. However, how the integration of antagonistic signals occurs upon NK cell–target cell interaction is not fully understood. Here we provide evidence that NK cell inhibition via the inhibitory receptor Ly49A is dependent on its relative colocalization at the nanometer scale with the activating receptor NKG2D upon immune synapse (IS) formation. NKG2D and Ly49A signal integration and colocalization were studied using NKG2D-GFP and Ly49A-RFP-expressing primary NK cells, forming ISs with NIH3T3 target cells, with or without the expression of single-chain trimer (SCT) H2-Dd and an extended form of SCT H2-Dd-CD4 MHC-I molecules. Nanoscale colocalization was assessed by Förster resonance energy transfer between NKG2D-GFP and Ly49A-RFP and measured for each synapse. In the presence of their respective cognate ligands, NKG2D and Ly49A colocalize at the nanometer scale, leading to NK cell inhibition. However, increasing the size of the Ly49A ligand reduced the nanoscale colocalization with NKG2D, consequently impairing Ly49A-mediated inhibition. Thus, our data shows that NK cell signal integration is critically dependent on the dimensions of NK cell ligand–receptor pairs by affecting their relative nanometer-scale colocalization at the IS. Our results together suggest that the balance of NK cell signals and NK cell responses is determined by the relative nanoscale colocalization of activating and inhibitory receptors in the immune synapse.
format Online
Article
Text
id pubmed-9198454
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-91984542022-06-16 Nanoscale Colocalization of NK Cell Activating and Inhibitory Receptors Controls Signal Integration Tomaz, David Pereira, Pedro Matos Guerra, Nadia Dyson, Julian Gould, Keith Henriques, Ricardo Front Immunol Immunology Natural killer (NK) cell responses depend on the balance of signals from inhibitory and activating receptors. However, how the integration of antagonistic signals occurs upon NK cell–target cell interaction is not fully understood. Here we provide evidence that NK cell inhibition via the inhibitory receptor Ly49A is dependent on its relative colocalization at the nanometer scale with the activating receptor NKG2D upon immune synapse (IS) formation. NKG2D and Ly49A signal integration and colocalization were studied using NKG2D-GFP and Ly49A-RFP-expressing primary NK cells, forming ISs with NIH3T3 target cells, with or without the expression of single-chain trimer (SCT) H2-Dd and an extended form of SCT H2-Dd-CD4 MHC-I molecules. Nanoscale colocalization was assessed by Förster resonance energy transfer between NKG2D-GFP and Ly49A-RFP and measured for each synapse. In the presence of their respective cognate ligands, NKG2D and Ly49A colocalize at the nanometer scale, leading to NK cell inhibition. However, increasing the size of the Ly49A ligand reduced the nanoscale colocalization with NKG2D, consequently impairing Ly49A-mediated inhibition. Thus, our data shows that NK cell signal integration is critically dependent on the dimensions of NK cell ligand–receptor pairs by affecting their relative nanometer-scale colocalization at the IS. Our results together suggest that the balance of NK cell signals and NK cell responses is determined by the relative nanoscale colocalization of activating and inhibitory receptors in the immune synapse. Frontiers Media S.A. 2022-06-01 /pmc/articles/PMC9198454/ /pubmed/35720315 http://dx.doi.org/10.3389/fimmu.2022.868496 Text en Copyright © 2022 Tomaz, Pereira, Guerra, Dyson, Gould and Henriques https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Tomaz, David
Pereira, Pedro Matos
Guerra, Nadia
Dyson, Julian
Gould, Keith
Henriques, Ricardo
Nanoscale Colocalization of NK Cell Activating and Inhibitory Receptors Controls Signal Integration
title Nanoscale Colocalization of NK Cell Activating and Inhibitory Receptors Controls Signal Integration
title_full Nanoscale Colocalization of NK Cell Activating and Inhibitory Receptors Controls Signal Integration
title_fullStr Nanoscale Colocalization of NK Cell Activating and Inhibitory Receptors Controls Signal Integration
title_full_unstemmed Nanoscale Colocalization of NK Cell Activating and Inhibitory Receptors Controls Signal Integration
title_short Nanoscale Colocalization of NK Cell Activating and Inhibitory Receptors Controls Signal Integration
title_sort nanoscale colocalization of nk cell activating and inhibitory receptors controls signal integration
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9198454/
https://www.ncbi.nlm.nih.gov/pubmed/35720315
http://dx.doi.org/10.3389/fimmu.2022.868496
work_keys_str_mv AT tomazdavid nanoscalecolocalizationofnkcellactivatingandinhibitoryreceptorscontrolssignalintegration
AT pereirapedromatos nanoscalecolocalizationofnkcellactivatingandinhibitoryreceptorscontrolssignalintegration
AT guerranadia nanoscalecolocalizationofnkcellactivatingandinhibitoryreceptorscontrolssignalintegration
AT dysonjulian nanoscalecolocalizationofnkcellactivatingandinhibitoryreceptorscontrolssignalintegration
AT gouldkeith nanoscalecolocalizationofnkcellactivatingandinhibitoryreceptorscontrolssignalintegration
AT henriquesricardo nanoscalecolocalizationofnkcellactivatingandinhibitoryreceptorscontrolssignalintegration