The Adaptor SAP Controls NK Cell Activation by Regulating the Enzymes Vav-1 and SHIP-1 and by Enhancing Conjugates with Target Cells

Dong, Zhongjun; Davidson, Dominique; Perez-Quintero, Luis Alberto; Kurosaki, Tomohiro; Swat, Wojciech; Veillette, André

doi:10.1016/j.immuni.2012.03.023

Cited by 125 publications

(215 citation statements)

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“…Ly108, but not CD84 or SLAM, inhibits Ag-specific T cell adhesion to both B cells and DCs It has recently been shown that, in the absence of SAP, SLAMF molecules such as Ly108 are associated with inhibitory phosphatases and dampen Ag-specific T-B adhesion (36,37,42,43). To examine whether the inhibitory function is a unique property of Ly108, we retrovirally transduced SLAM, CD84, and two main Ly108 isoforms into either WT or SAP KO T cells (Fig.…”

Section: Sap Is Required For Optimal T-b Adhesion Soon After Ligand Rmentioning

confidence: 99%

“…Several SLAMF receptors in NK cells were found to inhibit cytotoxicity when SAP and SAP-related adaptors are absent (33)(34)(35), leading to the notion of "switch" functions for SAP family adaptors in that they may physically or functionally compete with negative signaling modules associated with SLAMF receptors, and thereby convert inhibitory SLAMF functions into stimulatory actions (16). In support of this switching model, Veillette and colleagues (36) have shown that SAP simultaneously couples Fyn kinase to and uncouples lipid phosphatase SHIP-1 from SLAMF receptors in NK cells.…”

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confidence: 99%

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SAP-Regulated T Cell–APC Adhesion and Ligation-Dependent and -Independent Ly108–CD3ζ Interactions

Chu

Wang

Zhang

et al. 2014

The Journal of Immunology

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The germinal center response requires cooperation between Ag-specific T and B lymphocytes, which takes the form of long-lasting cell–cell conjugation in vivo. Signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) is required for stable cognate T–B cell conjugation, whereas SLAM family transmembrane (TM) receptor Ly108 may negatively regulate this process. We show that, other than phosphotyrosine-binding, SAP does not harbor motifs that recruit additional signaling intermediates to stabilize T–B adhesion. Ly108 dampens T cell adhesion to not only Ag-presenting B cells, but also dendritic cells by inhibiting CD3ζ phosphorylation through two levels of regulated Ly108–CD3ζ interactions. Constitutively associated with Src homology 2 domain–containing tyrosine phosphatase-1 even in SAP-competent cells, Ly108 is codistributed with the CD3 complex within a length scale of 100–200 nm on quiescent cells and can reduce CD3ζ phosphorylation in the absence of overt TCR stimulation or Ly108 ligation. When Ly108 is engaged in trans during cell–cell interactions, Ly108–CD3ζ interactions are promoted in a manner that uniquely depends on Ly108 TM domain, leading to more efficient CD3ζ dephosphorylation. Whereas replacement of the Ly108 TM domain still allows the constitutive, colocalization-dependent inhibition of CD3ζ phosphorylation, it abrogates the ligation-dependent Ly108–CD3ζ interactions and CD3ζ dephosphorylation, and it abolishes the suppression on Ag-triggered T–B adhesion. These results offer new insights into how SAP and Ly108 antagonistically modulate the strength of proximal TCR signaling and thereby control cognate T cell–APC interactions.

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Section: Sap Is Required For Optimal T-b Adhesion Soon After Ligand Rmentioning

confidence: 99%

mentioning

confidence: 99%

SAP-Regulated T Cell–APC Adhesion and Ligation-Dependent and -Independent Ly108–CD3ζ Interactions

Chu

Wang

Zhang

et al. 2014

The Journal of Immunology

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“…2014. 44: 1526-1534 Innate immunity 1531 activation, a crucial effector of 2B4-mediated inhibition is represented by SHIP-1 (and possibly SHIP-2), which negatively regulates downstream signals such as PLC-γ-mediated Ca 2+ fluxes [14,43]. According to our observation, in SAP −/− mice, members of the SLAM receptor family have been shown to inhibit NKG2D that, different to humans, associates with both DAP10 and DAP12 [45,46].…”

mentioning

confidence: 74%

XLP1 inhibitory effect by 2B4 does not affect DNAM‐1 and NKG2D activating pathways in NK cells

et al. 2014

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X-linked lymphoproliferative disease 1 (XLP1) is a rare congenital immunodeficiency caused by SH2D1A (Xq25) mutations resulting in lack or dysfunction of SLAM-associated protein adaptor molecule. In XLP1 patients, upon ligand (CD48) engagement, 2B4 delivers inhibitory signals that impair the cytolytic activity of NK (and T) cells. This causes the selective inability to control EBV infections and the occurrence of B-cell lymphomas. Here, we show that in the absence of SLAM-associated protein, co-engagement of 2B4 with different activating receptors, either by antibodies or specific ligands on target cells, inhibits different ITAM-dependent signaling pathways including activating killer Ig-like receptors. In XLP1 NK cells, 2B4 affected both the cytolytic and IFN-γ production capabilities, functions that were restored upon disruption of the 2B4/CD48 interactions. Notably, we provide evidence that 2B4 dysfunction does not affect the activity of DNAM-1 and NKG2D triggering receptors. Thus, while CD48 + B-EBV and lymphoma B cells devoid of NKG2D and DNAM-1 ligands were resistant to lysis, the preferential usage of these receptors allowed XLP1 NK cells to kill lymphomas that expressed sufficient amounts of the specific ligands. The study sheds new light on the XLP1 immunological defect and on the cross-talk of inhibitory 2B4 with triggering NK (and T) receptors. [6][7][8]. In general, virus-infected or neoplastic cells become susceptible to NK-cell-mediated lysis because they downregulate HLA-class I ("missing self-recognition") and upregulate ligands for activating NK receptors ("induced self-recognition") [9]. X-linked lymphoproliferative disease 1 (XLP1, Duncan disease, OMIM#308240) is a rare congenital immunodeficiency caused by mutations in SH2D1A (Xq25), the gene encoding the signaling lymphocyte activation molecule (SLAM) associated protein (SAP) [10,11]. SAP is a cytoplasmic adaptor protein that associates with members of the SLAM family, which includes SLAM (CD150), LY9 (CD229), CRACC (CD319), CD84, NTB-A (CD352), and 2B4 (CD244) [12]. 2B4 is a surface molecule expressed in NK and T lymphocytes specifically recognizing CD48, which is present solely on hematopoietic cells. 2B4 engagement causes tyrosine phosphorylation of immunoreceptor tyrosine-based switch motifs present in its cytoplasmic tail and recruitment of SAP, which transduces activating signals via Fyn-dependent processes [13,14]. In the presence of SAP, 2B4 potentiates the NCR-mediated signaling thus acting as a co-receptor molecule [15]. In the absence of SAP, 2B4 associates with protein tyrosine phosphatases and delivers inhibitory signals [16,17]. In NK cells, this occurs in physiological conditions such as during NK-cell development [18] and pregnancy [19]. On the other hand, in XLP1, the lack (or dysfunction) of SAP causes the selective inability to control infection by EBV, a γ-herpes virus that infects and sequesters itself in B cells [16,[20][21][22]. This causes severe manifestations including fulminant mononucleosis and B-cell lymphomas [...

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“…SLAM family receptors, principally expressed by hematopoietic cells, have Ig-like extracellular domains involved in homotypic (e.g., SLAM-SLAM) or heterotypic interactions (e.g., 2B4-CD48). Engagement of SLAM family receptors by self family ligands results in tyrosine phosphorylation of their immunoreceptor tyrosine-based switch motifs and the subsequent recruitment of SAP is thought to regulate signaling by two distinct mechanisms: 1) SAP transduction of signaling by binding the tyrosine kinase Fyn and protein kinase Cu (25,26,28,29); and 2) SAP inhibition of signaling by sterically hindering the docking of SH2 domain-containing phosphatases 1 and 2 and SHIP-1 (25,26,(30)(31)(32)(33). Thus, the absence of SAP may negate positive signaling and reinforce inhibitory signaling by SLAM family receptors.…”

Section: Il-17-secreting T Cells Was Shown To Be a T Cell-intrinsic Rmentioning

confidence: 99%

SLAM–SAP Signaling Promotes Differentiation of IL-17–Producing T Cells and Progression of Experimental Autoimmune Encephalomyelitis

Huang

Tsai

et al. 2014

The Journal of Immunology

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IL-17 plays critical roles in host defenses, combating bacterial and fungal infections, as well as the pathogenesis of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE). The signaling adaptor SAP is essential for normal immune homeostasis and mutations within SH2D1A, the locus encoding this protein, result in serious and sometimes fatal syndromes, including X-linked lymphoproliferative disease and severe cases of common variable immunodeficiency. However, the precise cellular basis of how SAP deficiency contributes to immune dysfunction remains incompletely understood. In this study, we found that CD4 and CD8 T cells lacking SAP had a diminished capacity to differentiate into IL-17–producing Th17 and T cytotoxic (Tc17) cells relative to wild-type lymphocytes. The use of costimulating SLAM Abs was found to augment the differentiation of IL-17–secreting effectors in wild-type but not Sh2d1a−/− splenic T cells under IL-17–polarizing conditions. In addition, SAP’s regulation of IL-17–secreting T cells was shown to be a T cell–intrinsic role, as purified naive Sh2d1a−/− CD4 and CD8 T cells were inherently defective at converting into Th17 and Tc17 cells in vitro and in vivo. Furthermore, Sh2d1a−/− mice were protected from EAE and exhibited greatly decreased numbers of CNS-infiltrating Th17 and Tc17 effector T cells and reduced disease severity. Collectively, these results suggest that SLAM–SAP signaling drives the differentiation and function of Th17 and Tc17 cells in vitro and in vivo and contributes to the pathogenesis of autoimmunity in EAE.

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The Adaptor SAP Controls NK Cell Activation by Regulating the Enzymes Vav-1 and SHIP-1 and by Enhancing Conjugates with Target Cells

Cited by 125 publications

References 58 publications

SAP-Regulated T Cell–APC Adhesion and Ligation-Dependent and -Independent Ly108–CD3ζ Interactions

SAP-Regulated T Cell–APC Adhesion and Ligation-Dependent and -Independent Ly108–CD3ζ Interactions

XLP1 inhibitory effect by 2B4 does not affect DNAM‐1 and NKG2D activating pathways in NK cells

SLAM–SAP Signaling Promotes Differentiation of IL-17–Producing T Cells and Progression of Experimental Autoimmune Encephalomyelitis

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