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Spatial clustering of receptors and signaling molecules regulates NK cell response to peptide repertoire changes

Spatial clustering of receptors and signaling molecules regulates NK cell response to peptide repertoire changes
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 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.
NK cells, peptide antagonism, KIR, HLA-C, signaling, modeling
1664-3224
1-11
Mbiribindi, Berenice
0f654cae-3ba2-42f3-93ec-0da44b5ada19
Mukherjee, Sayak
19a02392-75d8-418b-b6f0-bc095b162260
Wellington, Dannielle
675931a2-122b-464c-9aff-9be9879580fc
Das, Jayajit
989b840f-3503-41a1-aacb-65448949f07d
Khakoo, Salim I.
6c16d2f5-ae80-4d9b-9100-6bfb34ad0273
Mbiribindi, Berenice
0f654cae-3ba2-42f3-93ec-0da44b5ada19
Mukherjee, Sayak
19a02392-75d8-418b-b6f0-bc095b162260
Wellington, Dannielle
675931a2-122b-464c-9aff-9be9879580fc
Das, Jayajit
989b840f-3503-41a1-aacb-65448949f07d
Khakoo, Salim I.
6c16d2f5-ae80-4d9b-9100-6bfb34ad0273

Mbiribindi, Berenice, Mukherjee, Sayak, Wellington, Dannielle, Das, Jayajit and Khakoo, Salim I. (2019) Spatial clustering of receptors and signaling molecules regulates NK cell response to peptide repertoire changes. Frontiers in Immunology, 10, 1-11, [605]. (doi:10.3389/fimmu.2019.00605).

Record type: Article

Abstract

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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Accepted/In Press date: 7 March 2019
Published date: 5 April 2019
Keywords: NK cells, peptide antagonism, KIR, HLA-C, signaling, modeling

Identifiers

Local EPrints ID: 430660
URI: http://eprints.soton.ac.uk/id/eprint/430660
ISSN: 1664-3224
PURE UUID: 36c49c42-9cb5-430f-90f7-8185af011a45

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Date deposited: 08 May 2019 16:30
Last modified: 16 Dec 2019 17:38

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Contributors

Author: Berenice Mbiribindi
Author: Sayak Mukherjee
Author: Dannielle Wellington
Author: Jayajit Das
Author: Salim I. Khakoo

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