Soluble HLA class I molecules induce natural killer cell apoptosis through the engagement of CD8: evidence for a negative regulation exerted by members of the inhibitory receptor superfamily

Spaggiari, Grazia Maria; Contini, Paola; Carosio, Roberta; Arvigo, Marica; Ghio, Massimo; Oddone, Daniela; Dondero, Alessandra; Zocchi, Maria Raffaella; Puppo, Francesco; Indiveri, Francesco; Poggi, Alessandro

doi:10.1182/blood.v99.5.1706

Cited by 77 publications

(148 citation statements)

References 41 publications

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“…17 The addition of low concentrations of IL-2 (20 ng/ml) to the culture medium significantly increased the numbers of NK cells stimulated with 4 or 8 mg of iMICA protein for 3 or 5 days (Figure 2a). Previous reports have shown that soluble HLA class I molecules induce the apoptosis of NK cells through the engagement of CD8 22 or killing immunoglobulin-like receptors (KIR) 23 Because of the similarities between the a3 domains of classical HLA I molecules and MICA proteins, we investigated whether iMICA could promote the apoptosis of NK cells. As observed with ib2m, iMICA had no impact on the apoptosis of NK cells after 3 or 5 days of stimulation (Figure 2b).…”

Section: Mica Synergizes With Ilmentioning

confidence: 99%

Immobilized MHC class I chain-related protein A synergizes with IL-15 and soluble 4-1BB ligand to expand NK cells with high cytotoxicity ex vivo

Gong

Xiao

et al. 2010

Cell Mol Immunol

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Major histocompatibility complex (MHC) class I chain-related protein A (MICA), which is a ligand for human NKG2D, is expressed by a variety of epithelial tumor cells and promotes the activation of natural killer (NK), CD8 1 and cd-T cells. Although ectopic expression of MICA on tumor cells elicits anti-tumor responses, soluble MICA downregulates the activities of lymphocytes. In this study, we showed that recombinant, immobilized MICA (iMICA) molecules coated on plastic wells weakly promote peripheral NK cell activation, secretion of interferon (IFN)-c and degranulation without inducing apoptosis. In addition, iMICA synergized with IL-15 and soluble 4-1BB ligand (s4-1BBL) to expand NK cells 25-to 42-fold in a 13-day culture, whereas NK cells stimulated only with IL-15 and s4-1BBL expanded 10-to 16-fold. In contrast to NK cells expanded by IL-15 and s4-1BBL stimulation, NK cells expanded long term in the presence of iMICA exhibited increased cytotoxicity against leukemia cells. These results suggest that large numbers of NK cells with high cytotoxicity can be generated by stimulation with IL-15 and s4-1BBL in the presence of iMICA and that these cells can be used for adoptive cancer immunotherapy. Studies on the 4-1BB signaling pathway have shown that ligation of 4-1BB promotes the survival and multiplication of CD8 1 T and NK cells. 6 IL-15 is essential for the development and function of NK cells. 7 Coculture of NK cells with K562 cells ectopically coexpressing 4-1BB ligand (4-1BBL) and membrane-bound IL-15 effectively promotes the expansion of NK cells in vitro and mediates their cytotoxicity against some leukemia cells. 8,9 In addition, IL-15 upregulates the expression of NKG2D on NK and T cells, even in the presence of soluble NKG2DL. 10 IL-15 and NKG2D signals cross-regulate each other and

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Section: Mica Synergizes With Ilmentioning

confidence: 99%

Immobilized MHC class I chain-related protein A synergizes with IL-15 and soluble 4-1BB ligand to expand NK cells with high cytotoxicity ex vivo

Gong

Xiao

et al. 2010

Cell Mol Immunol

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“…We have demonstrated recently that NK cell triggering via HLA-I receptors, including CD8 Ag and the activating isoforms of inhibitory receptor superfamily (IRS) members, induces FasL release, which in turn leads to NK cell death (15,16). This finding would suggest that, not only FasL from tumor cells (13), but also FasL produced and released by NK cells can induce NK cell death.…”

mentioning

confidence: 92%

“…It is conceivable that during interaction between NK lymphocytes and tumor target cells additional surface molecules, besides NCR, may play a role in activating NK cell apoptosis (1,15). This does not allow us to consider NCR as molecules that directly trigger apoptosis.…”

Section: The Engagement Of Ncr With Specific Mabs Directly Triggers Nmentioning

confidence: 99%

“…sFasL present in culture SN after incubation with anti-NCR mAbs (antiNKp30, anti-NKp44, anti-NKp46) either in soluble form or with GAMcoated beads or on GAM-coated plates was evaluated by ELISA, as previously described (15,16). Briefly, 100 l of culture SN derived from NK cell clones after different incubation times (16), with medium alone, apoptosis-inducing anti-Fas mAb (CH-11, 3 g/ml), or 4-per-cell GAMcoated magnetic beads on NK cells preincubated with anti-NKp30 mAb, anti-NKp44 mAb, anti-NKp46 mAb, anti-CD16 mAb, or anti-CD54 mAb (14D12D2) were collected, added to a microtiter plate coated with antiFasL mAb NOK-2, and incubated for 45 min at room temperature (RT).…”

Section: Determination Of Soluble Fasl (Sfasl) In Culture Snmentioning

confidence: 99%

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Tumor-Induced Apoptosis of Human IL-2-Activated NK Cells: Role of Natural Cytotoxicity Receptors

Poggi¹,

Massaro

Negrini

et al. 2005

The Journal of Immunology

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We provide evidence that tumor cells can induce apoptosis of NK cells by engaging the natural cytotoxicity receptors (NCR) NKp30, NKp44, and NKp46. Indeed, the binding between NCR on NK cells and their putative ligands on tumor target cells led to NK cell apoptosis, and this event was abolished by blocking NCR/NCR-ligand interaction by anti-NCR-specific mAbs. The engagement of NCR induced up-regulation of Fas ligand (FasL) mRNA, FasL protein synthesis, and release. In turn, FasL interacting with Fas at NK cell surface causes NK cell suicide, as apoptosis of NK cells was inhibited by blocking FasL/Fas interaction with specific mAbs. Interestingly, NK cell apoptosis, but not killing of tumor target cells, is inhibited by cyclosporin A, suggesting that apoptosis and cytolysis are regulated by different biochemical pathways. These findings indicate that NCR are not only triggering molecules essential for antitumor activity, but also surface receptors involved in NK cell suicide.

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“…[14][15][16] However, we and others reported that sHLA-I molecules lead to activation-induced apoptosis, in vitro, mediated by synthesis and secretion of FasL and the consequent interaction with Fas expressed by allogeneic and autologous T and natural killer (NK) cells. [17][18][19][20][21] Furthermore, nanomolar concentrations of sHLA-I can prevent both alloreactive clones and primary T-cell cultures from recognizing and lysing their targets. 20 It has been reported that sHLA-I molecules bind to CD8 receptors expressed on cytotoxic effector lymphocytes, that is T and NK cells.…”

Section: Introductionmentioning

confidence: 99%

In vivo apoptosis of CD8+ lymphocytes in acute myeloid leukemia patients: involvement of soluble HLA-I and Fas ligand

et al. 2006

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In this study, we show that high serum levels of soluble human leukocyte antigens (HLA) class I molecules (sHLA-I, range: 0.7-1.7 lg/ml) and soluble Fas ligand (FasL, range: 0.4-1.9 ng/ml) are detected in patients with acute myeloid leukemia (AML) at diagnosis, compared with healthy donors (HD) (sHLA-I, range: 0.1-0.6 lg/ml; sFasL, range: 0.1-0.4 ng/ml). Patients' sera were able to induce transcription and secretion of FasL in CD8 þ T cells, followed by apoptosis in vitro; this apoptosis was inhibited by anti-HLA-I-specific monoclonal antibodies, suggesting that sHLA-I is responsible for cell death. These findings closely relate to the in vivo upregulation of FasL transcription observed in peripheral blood (PB) lymphocytes from AML patients; in the same cells, mRNA for the antiapoptotic proteins Bcl-2 and Bcl-x L was downregulated. Interestingly, caspase-8 and caspase-3, both downstream mediators of death receptorinduced apoptosis, were activated in CD8 þ cells of AML patients; one-third of these cells were already apoptotic in vivo, at variance with lymphocytes of HD. These data strongly suggest that in AML, increased levels of sHLA-I molecules may contribute to the elimination of potentially anti-tumor effector cells through a FasL/Fas interaction.

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Soluble HLA class I molecules induce natural killer cell apoptosis through the engagement of CD8: evidence for a negative regulation exerted by members of the inhibitory receptor superfamily

Cited by 77 publications

References 41 publications

Immobilized MHC class I chain-related protein A synergizes with IL-15 and soluble 4-1BB ligand to expand NK cells with high cytotoxicity ex vivo

Immobilized MHC class I chain-related protein A synergizes with IL-15 and soluble 4-1BB ligand to expand NK cells with high cytotoxicity ex vivo

Tumor-Induced Apoptosis of Human IL-2-Activated NK Cells: Role of Natural Cytotoxicity Receptors

In vivo apoptosis of CD8+ lymphocytes in acute myeloid leukemia patients: involvement of soluble HLA-I and Fas ligand

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