The Size of Activating and Inhibitory Killer Ig-like Receptor Nanoclusters Is Controlled by the Transmembrane Sequence and Affects Signaling

Oszmiana, Anna; Williamson, David J.; Cordoba, Shaun-Paul; Morgan, D. O.; Kennedy, Paul K.; Stacey, Kevin; Davis, Daniel M.

doi:10.1016/j.celrep.2016.04.075

Cited by 55 publications

(81 citation statements)

References 50 publications

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“…Further, phosphorylated KIR molecules are not distributed uniformly; rather, they are localized in discrete microclusters within the larger KIR cluster at the inhibitory synapses . In a recent study with super‐resolution microscopy, it is seen that KIR organizes into nanoclusters, and that SHP‐1 preferentially associates with larger KIR nanoclusters . The implication of such distribution of phosphorylated KIR at inhibitory synapses is not understood.…”

Section: Inhibition Of Nk Cell Cytotoxicitymentioning

confidence: 99%

Natural killer cell cytotoxicity and its regulation by inhibitory receptors

2018

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Natural killer (NK) cells express an array of germ-line encoded receptors that are capable of triggering cytotoxicity. NK cells tend to express many members of a given family of signalling molecules. The presence of many activating receptors and many members of a given family of signalling molecules can enable NK cells to detect different kinds of target cells, and to mount different kinds of responses. This contributes also to the robustness of NK cells responses; cytotoxic functions of NK cells often remain unaffected in the absence of selected signalling molecules. NK cells express many MHC-I-specific inhibitory receptors. Signals from MHC-I-specific inhibitory receptors tightly control NK cell cytotoxicity and, paradoxically, maintain NK cells in a state of proper responsiveness. This review provides a brief overview of the events that underlie NK cell activation, and how signals from inhibitory receptors intercept NK cell activation to prevent inappropriate triggering of cytotoxicity.

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Section: Inhibition Of Nk Cell Cytotoxicitymentioning

confidence: 99%

Natural killer cell cytotoxicity and its regulation by inhibitory receptors

2018

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“…A single dimorphism in the transmembrane region determines the signalling capacity; allotypes with R245 transduce a functional inhibitory signal and those with C245 have reduced inhibitory signalling 112. Super‐resolution microscopy has revealed that the nanoscale organization of KIR at cell surfaces depends on the transmembrane sequence, which in turn affects downstream signalling 113. Further modifying the functional range of KIR2DL1 are polymorphisms in the extracellular and cytoplasmic domains that regulate avidity and specificity, as well as the level of cell‐surface expression (Fig.…”

Section: Kir Ligand Bindingmentioning

confidence: 99%

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

et al. 2016

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SummaryKiller‐cell immunoglobulin‐like receptors (KIRs) are components of two fundamental biological systems essential for human health and survival. First, they contribute to host immune responses, both innate and adaptive, through their expression by natural killer cells and T cells. Second, KIR play a key role in regulating placentation, and hence reproductive success. Analogous to the diversity of their human leucocyte antigen class I ligands, KIR are extremely polymorphic. In this review, we describe recent developments, fuelled by methodological advances, that are helping to decipher the KIR system in terms of haplotypes, polymorphisms, expression patterns and their ligand interactions. These developments are delivering deeper insight into the relevance of KIR in immune system function, evolution and disease.

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“…The signaling cascade will only be triggered if there is a true interaction. The degree of receptor/ligand clustering might also influence the down-stream signaling, as shown by Oszmiana et al (80). Therefore, the reporter cells may be a more physiological system compared to Fc proteins or tetramers.…”

Section: Discussionmentioning

confidence: 93%

Modulation of Human Leukocyte Antigen-C by Human Cytomegalovirus Stimulates KIR2DS1 Recognition by Natural Killer Cells

et al. 2017

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The interaction of inhibitory killer cell Ig-like receptors (KIRs) with human leukocyte antigen (HLA) class I molecules has been characterized in detail. By contrast, activating members of the KIR family, although closely related to inhibitory KIRs, appear to interact weakly, if at all, with HLA class I. KIR2DS1 is the best studied activating KIR and it interacts with C2 group HLA-C (C2-HLA-C) in some assays, but not as strongly as KIR2DL1. We used a mouse 2B4 cell reporter system, which carries NFAT-green fluorescent protein with KIR2DS1 and a modified DAP12 adaptor protein. KIR2DS1 reporter cells were not activated upon coculture with 721.221 cells transfected with different HLA-C molecules, or with interferon-γ stimulated primary dermal fibroblasts. However, KIR2DS1 reporter cells and KIR2DS1+ primary natural killer (NK) cells were activated by C2-HLA-C homozygous human fetal foreskin fibroblasts (HFFFs) but only after infection with specific clones of a clinical strain of human cytomegalovirus (HCMV). Active viral gene expression was required for activation of both cell types. Primary NKG2A−KIR2DS1+ NK cell subsets degranulated after coculture with HCMV-infected HFFFs. The W6/32 antibody to HLA class I blocked the KIR2DS1 reporter cell interaction with its ligand on HCMV-infected HFFFs but did not block interaction with KIR2DL1. This implies a differential recognition of HLA-C by KIR2DL1 and KIR2DS1. The data suggest that modulation of HLA-C by HCMV is required for a potent KIR2DS1-mediated NK cell activation.

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The Size of Activating and Inhibitory Killer Ig-like Receptor Nanoclusters Is Controlled by the Transmembrane Sequence and Affects Signaling

Cited by 55 publications

References 50 publications

Natural killer cell cytotoxicity and its regulation by inhibitory receptors

Natural killer cell cytotoxicity and its regulation by inhibitory receptors

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

Modulation of Human Leukocyte Antigen-C by Human Cytomegalovirus Stimulates KIR2DS1 Recognition by Natural Killer Cells

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