Genetic diversity affects the nanoscale membrane organization and signaling of natural killer cell receptorsCitation formats

  • External authors:
  • Philippa Kennedy
  • Charlotte Barthen
  • David Williamson
  • William Pitkeathly
  • Joshua Cumming
  • Kevin Stacey
  • Hugo G. Hilton
  • Mary Carrington
  • Peter Parham

Standard

Genetic diversity affects the nanoscale membrane organization and signaling of natural killer cell receptors. / Kennedy, Philippa; Barthen, Charlotte; Williamson, David et al.

In: Science Signaling, 12.2019.

Research output: Contribution to journalArticlepeer-review

Harvard

Kennedy, P, Barthen, C, Williamson, D, Pitkeathly, W, Hazime, K, Cumming, J, Stacey, K, Hilton, HG, Carrington, M, Parham, P & Davis, DM 2019, 'Genetic diversity affects the nanoscale membrane organization and signaling of natural killer cell receptors', Science Signaling. https://doi.org/10.1126/scisignal.aaw9252

APA

Kennedy, P., Barthen, C., Williamson, D., Pitkeathly, W., Hazime, K., Cumming, J., Stacey, K., Hilton, H. G., Carrington, M., Parham, P., & Davis, D. M. (2019). Genetic diversity affects the nanoscale membrane organization and signaling of natural killer cell receptors. Science Signaling. https://doi.org/10.1126/scisignal.aaw9252

Vancouver

Kennedy P, Barthen C, Williamson D, Pitkeathly W, Hazime K, Cumming J et al. Genetic diversity affects the nanoscale membrane organization and signaling of natural killer cell receptors. Science Signaling. 2019 Dec. Epub 2019 Dec 17. doi: 10.1126/scisignal.aaw9252

Author

Kennedy, Philippa ; Barthen, Charlotte ; Williamson, David et al. / Genetic diversity affects the nanoscale membrane organization and signaling of natural killer cell receptors. In: Science Signaling. 2019.

Bibtex

@article{0a07fe9c84e54aec808939cc120ff67b,
title = "Genetic diversity affects the nanoscale membrane organization and signaling of natural killer cell receptors",
abstract = "Genetic diversity in human natural killer (NK) cell receptors is linked to resistance and susceptibility to many diseases, but the underlying mechanisms remain unclear. The effect of this diversity on the nanoscale organization of killer cell immunoglobulin (Ig)-like receptors (KIRs) has yet to be tested. Here, using superresolution microscopy, we found that inhibitory KIRs encoded by different genes and alleles were organized differently at the surface of primaryhuman NK cells. KIRs that were found at low abundance assembled into smaller clusters than those formed by KIRs that were more highly abundant, and at low abundance there was a greater proportion of KIRs in clusters. Upon receptor triggering, a structured interface called an immune synapse assembles, which facilitates signal integration and controls the NK cell response. Here, low-abundance receptors exhibited less phosphorylation of downstream hosphatase SHP-1 but more phosphorylation of adaptor protein Crk than did high-abundance receptors. In cells with greater KIR abundance, SHP-1 dephosphorylated Crk, which potentiated the NK cell spreading response during activation. Thus, genetic variation modulates both the abundance and nanoscaleorganization of inhibitory KIRs. In other words, as well as the number of receptors at the cell surface varying with genotype, the way in which these receptors are organized in the membrane also varies. Essentially, a change in the average surface abundance of a protein at the cell surface is a coarse descriptor entwined with changes in local nanoscale clustering. Altogether, our data indicate that genetic diversity in inhibitory KIRs affects membrane-proximal signaling and surprisingly, the formation of activating immune synapses.",
author = "Philippa Kennedy and Charlotte Barthen and David Williamson and William Pitkeathly and Khodor Hazime and Joshua Cumming and Kevin Stacey and Hilton, {Hugo G.} and Mary Carrington and Peter Parham and Davis, {Daniel M}",
year = "2019",
month = dec,
doi = "10.1126/scisignal.aaw9252",
language = "English",
journal = "Science Signaling",
issn = "1945-0877",
publisher = "American Association for the Advancement of Science (A A A S)",

}

RIS

TY - JOUR

T1 - Genetic diversity affects the nanoscale membrane organization and signaling of natural killer cell receptors

AU - Kennedy, Philippa

AU - Barthen, Charlotte

AU - Williamson, David

AU - Pitkeathly, William

AU - Hazime, Khodor

AU - Cumming, Joshua

AU - Stacey, Kevin

AU - Hilton, Hugo G.

AU - Carrington, Mary

AU - Parham, Peter

AU - Davis, Daniel M

PY - 2019/12

Y1 - 2019/12

N2 - Genetic diversity in human natural killer (NK) cell receptors is linked to resistance and susceptibility to many diseases, but the underlying mechanisms remain unclear. The effect of this diversity on the nanoscale organization of killer cell immunoglobulin (Ig)-like receptors (KIRs) has yet to be tested. Here, using superresolution microscopy, we found that inhibitory KIRs encoded by different genes and alleles were organized differently at the surface of primaryhuman NK cells. KIRs that were found at low abundance assembled into smaller clusters than those formed by KIRs that were more highly abundant, and at low abundance there was a greater proportion of KIRs in clusters. Upon receptor triggering, a structured interface called an immune synapse assembles, which facilitates signal integration and controls the NK cell response. Here, low-abundance receptors exhibited less phosphorylation of downstream hosphatase SHP-1 but more phosphorylation of adaptor protein Crk than did high-abundance receptors. In cells with greater KIR abundance, SHP-1 dephosphorylated Crk, which potentiated the NK cell spreading response during activation. Thus, genetic variation modulates both the abundance and nanoscaleorganization of inhibitory KIRs. In other words, as well as the number of receptors at the cell surface varying with genotype, the way in which these receptors are organized in the membrane also varies. Essentially, a change in the average surface abundance of a protein at the cell surface is a coarse descriptor entwined with changes in local nanoscale clustering. Altogether, our data indicate that genetic diversity in inhibitory KIRs affects membrane-proximal signaling and surprisingly, the formation of activating immune synapses.

AB - Genetic diversity in human natural killer (NK) cell receptors is linked to resistance and susceptibility to many diseases, but the underlying mechanisms remain unclear. The effect of this diversity on the nanoscale organization of killer cell immunoglobulin (Ig)-like receptors (KIRs) has yet to be tested. Here, using superresolution microscopy, we found that inhibitory KIRs encoded by different genes and alleles were organized differently at the surface of primaryhuman NK cells. KIRs that were found at low abundance assembled into smaller clusters than those formed by KIRs that were more highly abundant, and at low abundance there was a greater proportion of KIRs in clusters. Upon receptor triggering, a structured interface called an immune synapse assembles, which facilitates signal integration and controls the NK cell response. Here, low-abundance receptors exhibited less phosphorylation of downstream hosphatase SHP-1 but more phosphorylation of adaptor protein Crk than did high-abundance receptors. In cells with greater KIR abundance, SHP-1 dephosphorylated Crk, which potentiated the NK cell spreading response during activation. Thus, genetic variation modulates both the abundance and nanoscaleorganization of inhibitory KIRs. In other words, as well as the number of receptors at the cell surface varying with genotype, the way in which these receptors are organized in the membrane also varies. Essentially, a change in the average surface abundance of a protein at the cell surface is a coarse descriptor entwined with changes in local nanoscale clustering. Altogether, our data indicate that genetic diversity in inhibitory KIRs affects membrane-proximal signaling and surprisingly, the formation of activating immune synapses.

U2 - 10.1126/scisignal.aaw9252

DO - 10.1126/scisignal.aaw9252

M3 - Article

JO - Science Signaling

JF - Science Signaling

SN - 1945-0877

ER -