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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. Here, we tested the effect of this diversity on the nanoscale organization of killer cell immunoglobulin-like receptors (KIRs). Using superresolution microscopy, we found that inhibitory KIRs encoded by different genes and alleles were organized differently at the surface of primary human 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 the immune synapse assembles, which facilitates signal integration and controls NK cell responses. Here, triggering of low-abundance receptors resulted in less phosphorylation of the downstream phosphatase SHP-1 but more phosphorylation of the adaptor protein Crk than did triggering of high-abundance receptors. In cells with greater KIR abundance, SHP-1 dephosphorylated Crk, which potentiated NK cell spreading during activation. Thus, genetic variation modulates both the abundance and nanoscale organization of inhibitory KIRs. That is, 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. Together, our data indicate that genetic diversity in inhibitory KIRs affects membrane-proximal signaling and, unexpectedly, the formation of activating immune synapses.

journal_name

Sci Signal

journal_title

Science signaling

authors

Kennedy PR,Barthen C,Williamson DJ,Pitkeathly WTE,Hazime KS,Cumming J,Stacey KB,Hilton HG,Carrington M,Parham P,Davis DM

doi

10.1126/scisignal.aaw9252

subject

Has Abstract

pub_date

2019-12-17 00:00:00

issue

612

eissn

1945-0877

issn

1937-9145

pii

12/612/eaaw9252

journal_volume

12

pub_type

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