Essential function for SAP family adaptors in the surveillance of hematopoietic cells by natural killer cells

Dong, Zhongjun; Cruz-Munoz, Mario-Ernesto; Zhong, Ming-Chao; Chen, Riyan; Latour, Sylvain; Veillette, André

doi:10.1038/ni.1763

Cited by 123 publications

(208 citation statements)

References 48 publications

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“…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].…”

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 75%

“…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].It is of note that the functional independency of NKG2D and DNAM-1 from 2B4 could be relevant also in NK-cell physiology and in XLP1 T-cell biology. Indeed, in peculiar microenvironments such as during NK-cell development [18] and pregnancy [19], SAP − immature or decidual NK lymphocytes might interact with bystander CD48 + hematological cells expressing different repertoires of NKG2D and DNAM-1 ligands.…”

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confidence: 75%

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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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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 75%

mentioning

confidence: 75%

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

et al. 2014

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“…In contrast, our results clearly identify that Ly49 ITIM signaling is required for NK-cell licensing, which highlights the need to better characterize the signaling pathways downstream of the Ly49 ITIM to differentiate between the arming and disarming hypotheses. Moreover, it will be important to investigate whether context can influence ITIM signaling similar to how the immunoreceptor tyrosine-based switch motif of SLAM family receptors can signal through distinct pathways to activate or inhibit NK cells depending on the setting (37). A previous study showed that NK cells from NKC KD mice express reduced levels of Ly49s due to concatemer insertion in the NKC, which leads to impaired killing of MHC-I-deficient splenocytes and tumor cell lines.…”

Section: Discussionmentioning

confidence: 99%

Immunoreceptor tyrosine-based inhibitory motif–dependent functions of an MHC class I-specific NK cell receptor

Bern

Beckman

Ebihara

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) cells express MHC class I (MHC-I)-specific receptors, such as Ly49A, that inhibit killing of cells expressing self–MHC-I. Self–MHC-I also “licenses” NK cells to become responsive to activating stimuli and regulates the surface level of NK-cell inhibitory receptors. However, the mechanisms of action resulting from these interactions of the Ly49s with their MHC-I ligands, particularly in vivo, have been controversial. Definitive studies could be derived from mice with targeted mutations in inhibitory Ly49s, but there are inherent challenges in specifically altering a single gene within a multigene family. Herein, we generated a knock-in mouse with a targeted mutation in the immunoreceptor tyrosine-based inhibitory motif (ITIM) of Ly49A that abolished the inhibitory function of Ly49A in cytotoxicity assays. This mutant Ly49A caused a licensing defect in NK cells, but the surface expression of Ly49A was unaltered. Moreover, NK cells that expressed this mutant Ly49A exhibited an altered inhibitory receptor repertoire. These results demonstrate that Ly49A ITIM signaling is critical for NK-cell effector inhibition, licensing, and receptor repertoire development.

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“…On NK cells, CD319 and CD229 act as coactivating receptors, which results in increased cytotoxicity against targets cells expressing CD319 and CD229 (35,36), whereas, on B cells, ligation of CD319 induces proliferation and cytokine production (37). In contrast, no study of the function of SLAM receptors on pDCs has been reported.…”

Section: Altered Expression Of Cd319 and Cd229 On Pdcs And Nk Cells Fmentioning

confidence: 99%

Systemic Lupus Erythematosus Immune Complexes Increase the Expression of SLAM Family Members CD319 (CRACC) and CD229 (LY-9) on Plasmacytoid Dendritic Cells and CD319 on CD56dim NK Cells

Hagberg

Theorell

Schlums

et al. 2013

The Journal of Immunology

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Patients with systemic lupus erythematosus (SLE) display an activated type I IFN system due to unceasing IFN-α release from plasmacytoid dendritic cells (pDCs) stimulated by nucleic acid–containing immune complexes (ICs). NK cells strongly promote the IFN-α production by pDCs; therefore, we investigated surface molecules that could be involved in the pDC–NK cell cross-talk. In human PBMCs stimulated with RNA-containing ICs (RNA-ICs), the expression of the signaling lymphocyte activation molecule (SLAM) family receptors CD319 and CD229 on pDCs and CD319 on CD56dim NK cells was selectively increased. Upregulation of CD319 and CD229 on RNA-IC–stimulated pDCs was induced by NK cells or cytokines (e.g., GM-CSF, IL-3). IFN-α–producing pDCs displayed a higher expression of SLAM molecules compared with IFN-α− pDCs. With regard to signaling downstream of SLAM receptors, pDCs expressed SHIP-1, SHP-1, SHP-2, and CSK but lacked SLAM-associated protein (SAP) and Ewing’s sarcoma-activated transcript 2 (EAT2), indicating that these receptors may act as inhibitory receptors on pDCs. Furthermore, pDCs from patients with SLE had decreased expression of CD319 on pDCs and CD229 on CD56dim NK cells, but RNA-IC stimulation increased CD319 and CD229 expression. In conclusion, this study reveals that the expression of the SLAM receptors CD319 and CD229 is regulated on pDCs and NK cells by lupus ICs and that the expression of these receptors is specifically altered in SLE. These results, together with the observed genetic association between the SLAM locus and SLE, suggest a role for CD319 and CD229 in the SLE disease process.

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Essential function for SAP family adaptors in the surveillance of hematopoietic cells by natural killer cells

Cited by 123 publications

References 48 publications

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

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

Immunoreceptor tyrosine-based inhibitory motif–dependent functions of an MHC class I-specific NK cell receptor

Systemic Lupus Erythematosus Immune Complexes Increase the Expression of SLAM Family Members CD319 (CRACC) and CD229 (LY-9) on Plasmacytoid Dendritic Cells and CD319 on CD56dim NK Cells

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