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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.00605

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

  • 1Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, United Kingdom
  • 2Institute of Bioinformatics and Applied Biotechnology, India
  • 3Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, United Kingdom
  • 4Battelle Center for Mathematical Medicine, The Research Institute at the Nationwide Children’s Hospital, United States
  • 5Department of Pediatrics, Wexner College of Medicine, The Ohio State University, United States
  • 6The Ohio State University, United States

Natural Killer (NK) cell activation requires the 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 cells 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 modelling, 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.

Keywords: NK cells, KIR, HLA-C, Peptide Antagonism, modeling, signaling

Received: 21 Jan 2019; Accepted: 07 Mar 2019.

Edited by:

Eleanor Riley, Roslin Institute, University of Edinburgh, United Kingdom

Reviewed by:

Stephen K. Anderson, National Cancer Institute at Frederick, United States
Kerry S. Campbell, Fox Chase Cancer Center, United States  

Copyright: © 2019 Mbiribindi, Mukherjee, Wellington, Das and Khakoo. 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.

* Correspondence:
Dr. Jayajit Das, Battelle Center for Mathematical Medicine, The Research Institute at the Nationwide Children’s Hospital, Columbus, United States, Jayajit.Das@nationwidechildrens.org
Prof. Salim I. Khakoo, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, SO171BJ, Hampshire, United Kingdom, S.I.Khakoo@soton.ac.uk