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Spatial Clustering of Receptors and Signaling Molecules Regulates NK Cell Response to Peptide Repertoire Changes

Natural Killer (NK) cell activation requires integration of inhibitory and activating signaling. Inhibitory signals are determined by members of the killer cell immunoglobulin-like receptor (KIR) family, which have major histocompatibility complex (MHC) class I ligands. Loss of this inhibitory signa...

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Autores principales: Mbiribindi, Berenice, Mukherjee, Sayak, Wellington, Dannielle, Das, Jayajit, Khakoo, Salim I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460049/
https://www.ncbi.nlm.nih.gov/pubmed/31024524
http://dx.doi.org/10.3389/fimmu.2019.00605
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author Mbiribindi, Berenice
Mukherjee, Sayak
Wellington, Dannielle
Das, Jayajit
Khakoo, Salim I.
author_facet Mbiribindi, Berenice
Mukherjee, Sayak
Wellington, Dannielle
Das, Jayajit
Khakoo, Salim I.
author_sort Mbiribindi, Berenice
collection PubMed
description Natural Killer (NK) cell activation requires integration of inhibitory and activating signaling. Inhibitory signals are determined by members of the killer cell immunoglobulin-like receptor (KIR) family, which have major histocompatibility complex (MHC) class I ligands. Loss of this inhibitory signal leads to NK cell activation. Thus, down-regulation of MHC I during viral infection or cancer induces NK cell activation. However, NK cell activation in the presence of MHC-I has been demonstrated for HLA-C(*)0102 through changes in its peptide content: “peptide antagonism.” Here we identify an antagonist peptide for HLA-C(*)0304 suggesting that peptide antagonism is a generalizable phenomenon and, using a combination of mathematical modeling, confocal imaging, and immune-assays, we quantitatively determine mechanisms that underlie peptide antagonism in inhibitory KIR2DL2/3 signaling. These data provide a mechanism for NK cell activation based on a reduction of inhibitory signaling in the presence of preserved levels of MHC class I.
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spelling pubmed-64600492019-04-25 Spatial Clustering of Receptors and Signaling Molecules Regulates NK Cell Response to Peptide Repertoire Changes Mbiribindi, Berenice Mukherjee, Sayak Wellington, Dannielle Das, Jayajit Khakoo, Salim I. Front Immunol Immunology Natural Killer (NK) cell activation requires integration of inhibitory and activating signaling. Inhibitory signals are determined by members of the killer cell immunoglobulin-like receptor (KIR) family, which have major histocompatibility complex (MHC) class I ligands. Loss of this inhibitory signal leads to NK cell activation. Thus, down-regulation of MHC I during viral infection or cancer induces NK cell activation. However, NK cell activation in the presence of MHC-I has been demonstrated for HLA-C(*)0102 through changes in its peptide content: “peptide antagonism.” Here we identify an antagonist peptide for HLA-C(*)0304 suggesting that peptide antagonism is a generalizable phenomenon and, using a combination of mathematical modeling, confocal imaging, and immune-assays, we quantitatively determine mechanisms that underlie peptide antagonism in inhibitory KIR2DL2/3 signaling. These data provide a mechanism for NK cell activation based on a reduction of inhibitory signaling in the presence of preserved levels of MHC class I. Frontiers Media S.A. 2019-04-05 /pmc/articles/PMC6460049/ /pubmed/31024524 http://dx.doi.org/10.3389/fimmu.2019.00605 Text en Copyright © 2019 Mbiribindi, Mukherjee, Wellington, Das and Khakoo. http://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
Mbiribindi, Berenice
Mukherjee, Sayak
Wellington, Dannielle
Das, Jayajit
Khakoo, Salim I.
Spatial Clustering of Receptors and Signaling Molecules Regulates NK Cell Response to Peptide Repertoire Changes
title Spatial Clustering of Receptors and Signaling Molecules Regulates NK Cell Response to Peptide Repertoire Changes
title_full Spatial Clustering of Receptors and Signaling Molecules Regulates NK Cell Response to Peptide Repertoire Changes
title_fullStr Spatial Clustering of Receptors and Signaling Molecules Regulates NK Cell Response to Peptide Repertoire Changes
title_full_unstemmed Spatial Clustering of Receptors and Signaling Molecules Regulates NK Cell Response to Peptide Repertoire Changes
title_short Spatial Clustering of Receptors and Signaling Molecules Regulates NK Cell Response to Peptide Repertoire Changes
title_sort spatial clustering of receptors and signaling molecules regulates nk cell response to peptide repertoire changes
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460049/
https://www.ncbi.nlm.nih.gov/pubmed/31024524
http://dx.doi.org/10.3389/fimmu.2019.00605
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