Sequential Involvement of Lck and SHP-1 with MHC-Recognizing Receptors on NK Cells Inhibits FcR-Initiated Tyrosine Kinase Activation

Binstadt, Bryce A; Brumbaugh, Kathryn M.; Dick, Chris; Scharenberg, Andrew M.; Williams, Brandi L.; Colonna, Marco; Lanier, Lewis L.; Kinét, Jean Pierre; Abraham, Robert T.; Leibson, Paul J.

doi:10.1016/s1074-7613(00)80276-9

Cited by 303 publications

(229 citation statements)

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“…Rabbit polyclonal antiserum to Itk was obtained after immunization of rabbits with KLH-conjugated Itk peptide 145-170 (QYDPTKNASKKPLPPTPEDNRRPLWE; Cocalico Biologicals). Rabbit polyclonal Abs to PLC␥2, Vav1, and Zap70 have been described previously (15)(16)(17).…”

Section: Reagents Cells and Absmentioning

confidence: 99%

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

Khurana

Arneson

Schoon

et al. 2007

The Journal of Immunology

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NK cells are effector lymphocytes that can recognize and eliminate virally infected and transformed cells. NK cells express distinct activating receptors, including an ITAM-containing FcR complex that recognizes Ab-coated targets, and the DNAX-activating protein of 10 kDa-containing NKG2D receptor complex that recognizes stress-induced ligands. The regulatory role of specific tyrosine kinases in these pathways is incompletely understood. In this study, we show that, in activated human NK cells, the tyrosine kinase IL-2-inducible T cell kinase (Itk), differentially regulates distinct NK-activating receptors. Enhanced expression of Itk leads to increases in calcium mobilization, granule release, and cytotoxicity upon stimulation of the ITAM-containing FcR, suggesting that Itk positively regulates FcR-initiated cytotoxicity. In contrast, enhanced Itk expression decreases cytotoxicity and granule release downstream of the DNAX-activating protein of 10 kDa-containing NKG2D receptor, suggesting that Itk is involved in a pathway of negative regulation of NKG2D-initiated granule-mediated killing. Using a kinase mutant, we show that the catalytic activity of Itk is required for both the positive and negative regulation of these pathways. Complementary experiments where Itk expression was suppressed also showed differential regulation of the two pathways. These findings suggest that Itk plays a complex role in regulating the functions initiated by distinct NK cell-activating receptors. Moreover, understanding how these pathways may be differentially regulated has relevance in the setting of autoimmune diseases and antitumor immune responses where NK cells play key regulatory roles.

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Section: Reagents Cells and Absmentioning

confidence: 99%

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

Khurana

Arneson

Schoon

et al. 2007

The Journal of Immunology

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“…These inhibitory receptors include amongst other the CTLA-4 and CD22 expressed by T and B cells, respectively, murine FccRIIB on B and mast cells or the killer cell inhibitory receptors (KIR) on natural killer (NK) cells [1,2,3]. These receptors, upon being co-clustered with the activating receptors undergo phosphorylation of their ITIM tyrosine residues and recruit SH2 domain containing phosphatases, which interfere with the activating receptors' stimulus-response coupling cascade [1,3,4,5]. The mast cells function-associated antigen (MAFA), another inhibitory receptor has a C-type lectin domain in its extracellular part and, like the other members of the above family, its intracellular domain contains an ITIM sequence [6].…”

Section: Introductionmentioning

confidence: 99%

“…Clustering was found to be required and sufficient for inhibiting the secretory response to the type 1 receptor for IgE (FceRI) [7][8][9]. This is one important feature, which distinguishes MAFA as an inhibitory receptor from the majority of the other that require their coclustering with the activating receptors in order to induce inhibition [1][2][3][4].…”

Section: Introductionmentioning

confidence: 99%

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Regulation of mast cells’ secretory response by co‐clustering the Type 1 Fcϵ receptor with the mast cell function‐associated antigen

2005

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The mast cell function-associated antigen (MAFA) is a type II membrane glycoprotein first identified on rat mast cells and basophils. Clustering MAFA inhibits these cells' secretory response to the type 1 Fce receptor (FceRI) stimulus. To quantitatively characterize this inhibition and its dependence on MAFA-FceRI co-clustering, we investigated the secretory response of rat mucosal-type mast cells of the RBL 2H3 line carrying an IgE class, 2,4 dinitrophenyl (DNP) specific monoclonal antibody to DNPconjugated Fab and F(ab 0 ) 2 fragments of (1) mouse IgG, and (2) of the MAFA-specific, monoclonal antibody G63. The first reagent clusters FceRI-IgE complexes into oligomers by reacting with the DNP residues. The DNP conjugated G63 Fab and F(ab 0 ) 2 fragments, additionally aggregate MAFA and form FceRI-IgE-MAFA co-clusters. All experiments using these ligands were performed in the absence or presence of an excess of intact mAb G63, which clusters MAFA molecules. Empirical Hill functions were used to relate the secretory response of mast cells to the equilibrium concentrations of FceRI-IgE or MAFA clusters and co-clusters calculated as function of the employed ligands concentrations. This analysis of the experimental results indicates that coclustered MAFA molecules have a markedly higher inhibitory capacity than MAFAclusters alone. The molecular basis of the enhanced inhibition observed upon coclustering MAFA with the FceRI is most probably the increased concentration of the inhibitory cell components in the immediate proximity of the activation coupling elements.

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“…An important role for SHP-1 in the inhibitory pathway of mature NK cells is evident from several studies. The overexpression of a catalytically inactive SHP-1 mutant in human NK cell clones prevents MHC class I-mediated inhibition of natural killing and Ab-dependent cell-mediated cytotoxicity (8,9). Furthermore, NK cells from motheaten (me) and viable motheaten (me v ) mice that show complete and partial loss of SHP-1 enzymatic activity, respectively (10), are partially impaired in Ly49A-mediated inhibition of natural cytotoxicity (11).…”

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confidence: 99%

Impaired Natural Killing of MHC Class I-Deficient Targets by NK Cells Expressing a Catalytically Inactive Form of SHP-1

Lowin-Kropf

Kunz

Beermann³

et al. 2000

The Journal of Immunology

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NK cell function is negatively regulated by MHC class I-specific inhibitory receptors. Transduction of the inhibitory signal involves protein tyrosine phosphatases such as SHP-1 (SH2-containing protein tyrosine phosphatase-1). To investigate the role of SHP-1 for NK cell development and function, we generated mice expressing a catalytically inactive, dominant-negative mutant of SHP-1 (dnSHP-1). In this paper we show that expression of dnSHP-1 does not affect the generation of NK cells even though MHC receptor-mediated inhibition is partially impaired. Despite this defect, these NK cells do not kill syngeneic, normal target cells. In fact dnSHP-1-expressing NK cells are hyporesponsive toward MHC-deficient target cells, suggesting that non-MHC-specific NK cell activation is significantly reduced. In contrast, these NK cells mediate Ab-dependent cell-mediated cytotoxicity and prevent the engraftment with β2-microglobulin-deficient bone marrow cells. A similar NK cell phenotype is observed in viable motheaten (mev) mice, which show reduced SHP-1 activity due to a mutation in the Shp-1 gene. In addition, NK cells in both mouse strains show a tendency to express more inhibitory MHC-specific Ly49 receptors. Our results demonstrate the importance of SHP-1 for the generation of functional NK cells, which are able to react efficiently to the absence of MHC class I molecules from normal target cells. Therefore, SHP-1 may play an as-yet-unrecognized role in some NK cell activation pathways. Alternatively, a reduced capacity to transduce SHP-1-dependent inhibitory signals during NK cell development may be compensated by the down-modulation of NK cell triggering pathways.

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Sequential Involvement of Lck and SHP-1 with MHC-Recognizing Receptors on NK Cells Inhibits FcR-Initiated Tyrosine Kinase Activation

Cited by 303 publications

References 0 publications

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk

Regulation of mast cells’ secretory response by co‐clustering the Type 1 Fcϵ receptor with the mast cell function‐associated antigen

Impaired Natural Killing of MHC Class I-Deficient Targets by NK Cells Expressing a Catalytically Inactive Form of SHP-1

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