Matched Sizes of Activating and Inhibitory Receptor/Ligand Pairs Are Required for Optimal Signal Integration by Human Natural Killer Cells

Köhler, Karsten; Xiong, Shiqiu; Brzostek, Joanna; Mehrabi, Maryam; Eissmann, Philipp; Harrison, A.; Cordoba, Shaun-Paul; Oddos, Stéphane; Miloserdov, Vladimir; Gould, Keith G.; Burroughs, Nigel John; Merwe, P. Anton van der; Davis, Daniel M.

doi:10.1371/journal.pone.0015374

Cited by 51 publications

(71 citation statements)

References 59 publications

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“…It has also been proposed that the K-S mechanism is important for signal transduction by many other small receptors where signaling involves phosphorylation of cytoplasmic tyrosine residues by extrinsic membrane-associated Src tyrosine kinases. 11 Indeed, there is evidence to support a role for the K-S mechanism in the case of natural killer receptors, 38,39 CD28, 40 and Dectin-1. 41 A role in B-cell receptor triggering has also been proposed.…”

Section: Org Frommentioning

confidence: 99%

The large ectodomains of CD45 and CD148 regulate their segregation from and inhibition of ligated T-cell receptor

Cordoba

Choudhuri

Zhang

et al. 2013

Blood

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• The large extracellular domains of the tyrosine phosphatases CD45 and CD148 prevent them from inhibiting T-cell receptor triggering.• These domains are required for optimal segregation from the engaged T-cell receptor, supporting the kineticsegregation model of triggering.T-cell receptor (TCR) triggering results in a cascade of intracellular tyrosine phosphorylation events that ultimately leads to T-cell activation. It is dependent on changes in the relative activities of membrane-associated tyrosine kinases and phosphatases near the engaged TCR. CD45 and CD148 are transmembrane tyrosine phosphatases with large ectodomains that have activatory and inhibitory effects on TCR triggering. This study investigates whether and how the ectodomains of CD45 and CD148 modulate their inhibitory effect on TCR signaling. Expression in T cells of forms of these phosphatases with truncated ectodomains inhibited TCR triggering. In contrast, when these phosphatases were expressed with large ectodomains, they had no inhibitory effect. Imaging studies revealed that truncation of the ectodomains enhanced colocalization of these phosphatases with ligated TCR at the immunological synapse. Our results suggest that the large ectodomains of CD45 and CD148 modulate their inhibitory effect by enabling their passive, size-based segregation from ligated TCR, supporting the kinetic-segregation model of TCR triggering. (Blood. 2013;121(21):4295-4302) Introduction T cells are stimulated through the T-cell receptor (TCR) when it binds cognate peptide presented by a major histocompatibility complex molecule (pMHC) on another cell. As a consequence of ligation, immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic domains of the TCR/CD3 complex are phosphorylated by lymphocyte-specific protein tyrosine kinase (Lck). These phosphorylated ITAMs recruit z-chain-associated protein tyrosine kinase 70 to the membrane, and Zap-70 phosphorylates substrates such as linker of activated T cells (LAT). 1Despite the extensive research in this field, the mechanism by which the binding of TCR to pMHC leads to phosphorylation of TCR/CD3 ITAMs is still contested, and several models have been proposed. 2One common feature of some of these models is that TCR triggering is initiated by changes in the relative concentrations of membrane tyrosine kinases and phosphatases in the vicinity of ligated TCR. 2The principal membrane tyrosine phosphatases involved in regulating TCR-induced tyrosine phosphorylation are CD45 and CD148. 3 The importance of this dynamic equilibrium between kinase and phosphatase activity in TCR triggering was highlighted in studies that use phosphatase inhibitors such as pervanadate. [4][5][6] Treatment of T cells with these inhibitors alone, in the absence of any TCR ligand, was sufficient to induce full activation of TCR signaling pathways, ranging from early events such as phosphorylation of TCR ITAMs, Zap-70, and LAT to late events such as interleukin 2 (IL-2) production. [4][5][6] Several mechanisms have been propos...

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Section: Org Frommentioning

confidence: 99%

The large ectodomains of CD45 and CD148 regulate their segregation from and inhibition of ligated T-cell receptor

Cordoba

Choudhuri

Zhang

et al. 2013

Blood

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“…When there are two bound molecules in neighboring positions, which differ in size of the extracellular domain by more than 10 nm, the membrane is assumed to be in stress, as has been suggested by previous models of the T cell IS (33,(44)(45)(46) and recently in experimental studies of NK cell synapses (47). To model the effect of the stress, the probability for the molecule to move away from the other molecule is multiplied by a stress factor.…”

Section: Moleculesmentioning

confidence: 99%

Simulations of the NK Cell Immune Synapse Reveal that Activation Thresholds Can Be Established by Inhibitory Receptors Acting Locally

Kaplan

Kotzer

Almeida

et al. 2011

The Journal of Immunology

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NK cell activation is regulated by a balance between activating and inhibitory signals. To address the question of how these signals are spatially integrated, we created a computer simulation of activating and inhibitory NK cell immunological synapse (NKIS) assembly, implementing either a “quantity-based” inhibition model or a “distance-based” inhibition model. The simulations mimicked the observed molecule distributions in inhibitory and activating NKIS and yielded several new insights. First, the total signal is highly influenced by activating complex dissociation rates but not by adhesion and inhibitory complex dissociation rates. Second, concerted motion of receptors in clusters significantly accelerates NKIS maturation. Third, when the potential of a cis interaction between Ly49 receptors and MHC class I on murine NK cells was added to the model, the integrated signal as a function of receptor and ligand numbers was only slightly increased, at least up to the level of 50% cis-bound Ly49 receptors reached in the model. Fourth, and perhaps most importantly, the integrated signal behavior obtained when using the distance-based inhibition signal model was closer to the experimentally observed behavior, with an inhibition radius of the order 3–10 molecules. Microscopy to visualize Vav activation in NK cells on micropatterned surfaces of activating and inhibitory strips revealed that Vav is only locally activated where activating receptors are ligated within a single NK cell contact. Taken together, these data are consistent with a model in which inhibitory receptors act locally; that is, that every bound inhibitory receptor acts on activating receptors within a certain radius around it.

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“…However, KIR-HLA class I ligand mismatch can occur in an allogeneic setting when the donor's NK cells express KIRs that do not recognize the recipient's HLA class I molecules, resulting in diminished inhibitory signals for NK cells (18). In addition, when activating KIR, NKG2D and NCRs are ligated to their cognate ligands, the balance may be tipped towards activating signals, and this ultimately determines cytotoxic potency (19) and production of proinflammatory cytokines and chemokines. Thus, the therapeutic potential of NK cells against cancer was explored in vitro (20)(21)(22) and in vivo (23,24).…”

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confidence: 99%

NK Cells with KIR2DS2 Immunogenotype Have a Functional Activation Advantage To Efficiently Kill Glioblastoma and Prolong Animal Survival

Navarro

Kmiecik

Leiss

et al. 2014

The Journal of Immunology

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Glioblastomas (GBMs) are lethal brain cancers that are resistant to current therapies. We investigated the cytotoxicity of human allogeneic NK cells against patient-derived GBM in vitro and in vivo, as well as mechanisms mediating their efficacy. We demonstrate that KIR2DS2 immunogenotype NK cells were more potent killers, notwithstanding the absence of inhibitory killer Ig–like receptor (KIR)-HLA ligand mismatch. FACS-sorted and enriched KIR2DS2+ NK cell subpopulations retained significantly high levels of CD69 and CD16 when in contact with GBM cells at a 1:1 ratio and highly expressed CD107a and secreted more soluble CD137 and granzyme A. In contrast, KIR2DS2− immunogenotype donor NK cells were less cytotoxic against GBM and K562, and, similar to FACS-sorted or gated KIR2DS2− NK cells, significantly diminished CD16, CD107a, granzyme A, and CD69 when in contact with GBM cells. Furthermore, NK cell–mediated GBM killing in vitro depended upon the expression of ligands for the activating receptor NKG2D and was partially abrogated by Ab blockade. Treatment of GBM xenografts in NOD/SCID mice with NK cells from a KIR2DS2+ donor lacking inhibitory KIR-HLA ligand mismatch significantly prolonged the median survival to 163 d compared with vehicle controls (log-rank test, p = 0.0001), in contrast to 117.5 d (log-rank test, p = 0.0005) for NK cells with several inhibitory KIR-HLA ligand mismatches but lacking KIR2DS2 genotype. Significantly more CD56+CD16+ NK cells from a KIR2DS2+ donor survived in nontumor-bearing brains 3 wk after infusion compared with KIR2DS2− NK cells, independent of their proliferative capacity. In conclusion, KIR2DS2 identifies potent alloreactive NK cells against GBM that are mediated by commensurate, but dominant, activating signals.

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Matched Sizes of Activating and Inhibitory Receptor/Ligand Pairs Are Required for Optimal Signal Integration by Human Natural Killer Cells

Cited by 51 publications

References 59 publications

The large ectodomains of CD45 and CD148 regulate their segregation from and inhibition of ligated T-cell receptor

The large ectodomains of CD45 and CD148 regulate their segregation from and inhibition of ligated T-cell receptor

Simulations of the NK Cell Immune Synapse Reveal that Activation Thresholds Can Be Established by Inhibitory Receptors Acting Locally

NK Cells with KIR2DS2 Immunogenotype Have a Functional Activation Advantage To Efficiently Kill Glioblastoma and Prolong Animal Survival

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