The requirement for NKG2D in NK cell–mediated rejection of parental bone marrow grafts is determined by MHC class I expressed by the graft recipient

Beilke, Joshua; Benjamin, Jonathan; Lanier, Lewis L.

doi:10.1182/blood-2010-05-285031

Cited by 23 publications

(26 citation statements)

References 35 publications

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“…52 Although no dramatic difference was seen between mice treated with isotype control antibody and anti-NKG2D antibody at this time point, RAE-1 expression was markedly increased by day 14 posttransplantation in the isotype control-treated, but not the anti-NKG2D antibody-treated, group. This finding suggested that a window of opportunity might exist, where NKG2D is no longer important for GVHD because of the lack of ligand expression by normal tissue but is critical for enabling donor CD8…”

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confidence: 95%

NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT

Karimi¹,

Bryson²,

Richman³

et al. 2015

Blood

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• NKG2D enhances cytotoxicity and survival of CD8 1 T cells, which contributes to GVHD and GVT effects after allogeneic HSCT.• The temporally distinct expression pattern of NKG2D ligands may allow separation of GVHD and GVT effects by transient NKG2D blockade.In allogeneic hematopoietic stem cell transplantation (HSCT), controlling graft-versushost disease (GVHD) while maintaining graft-versus-tumor (GVT) responses is of critical importance. Using a mouse model of allogeneic HSCT, we hereby demonstrate that NKG2D expression by CD8 1 T cells plays a major role in mediating GVHD and GVT effects by promoting the survival and cytotoxic function of CD8 1 T cells. The expression of NKG2D ligands was not induced persistently on normal tissues of allogeneic HSCTrecipient mice treated with anti-NKG2D antibody, suggesting that transient NKG2D blockade might be sufficient to attenuate GVHD and allow CD8 1 T cells to regain their GVT function. Indeed, short-term treatment with anti-NKG2D antibody restored GVT effects while maintaining an attenuated GVHD state. NKG2D expression was also detected on CD8 1 T cells from allogeneic HSCT patients and trended to be higher in those with active GVHD. Together, these data support a novel role for NKG2D expression by CD8 1 T cells during allogeneic HSCT, which could be potentially therapeutically exploited to separate

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confidence: 95%

NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT

Karimi¹,

Bryson²,

Richman³

et al. 2015

Blood

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“…Fourth, the DNA damage pathway that is activated in response to ionizing radiation and chemotherapy is central in the upregulation of NKG2DL (23). Fifth, neutralization of the NKG2D receptors by antibodies prevents graft rejection in mice (24, 25). Finally, blockade of the NKG2D/NKG2DL interaction by antibodies directed against NKG2D, attenuate GVHD while allowing CD8 + T cells to regain their GVL activity (26).…”

Section: Introductionmentioning

confidence: 99%

Natural Killer Group 2, Member D/NKG2D Ligands in Hematopoietic Cell Transplantation

et al. 2017

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Natural killer group 2, member D (NKG2D) is an invariant activatory receptor present on subsets of natural killer and T lymphocytes. It stimulates the cytolytic effector response upon engagement of its various stress-induced ligands NKG2D ligands (NKG2DL). Malignant transformation and conditioning treatment prior to hematopoietic cell transplantation (HCT) are stress factors leading to the activation of the NKG2D/NKG2DL signaling in clinical settings. In the context of HCT, NKG2D-bearing cells can kill both tumor and healthy cells expressing NKG2DL. The NKG2D/NKG2DL engagement has therefore a key role in the regulation of one of the most salient issues in allogeneic HCT, i.e., maintaining a balance between graft-vs.-leukemia effect and graft-vs.-host disease. The present review summarizes the current state of our knowledge pertaining to the role of the NKG2D and NKG2DL in HCT.

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“…[31][32][33] To examine the effect of DOCK2 deficiency on BM transplantation, we used b2m 2/2 C57BL/6 mice as donors. As b2m 2/2 BM cells lack the expression BLOOD, 18 JULY 2013 x VOLUME 122, NUMBER 3…”

Section: Dock2 Deficiency Enables Engraftment Of Mhc Class I-deficienmentioning

confidence: 99%

The Rac activator DOCK2 regulates natural killer cell–mediated cytotoxicity in mice through the lytic synapse formation

Sakai

Tanaka

Yanagihara

et al. 2013

Blood

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Key Points• DOCK2-deficienct NK cells fail to effectively kill leukemia cells in vitro and major histocompatibility complex class I-deficient bone marrow cells in vivo.• Activating NK receptor-mediated Rac activation and the lytic synapse formation are severely impaired in DOCK2-deficient NK cells.Natural killer (NK) cells play an important role in protective immunity against viral infection and tumor progression, but they also contribute to rejection of bone marrow grafts via contact-dependent cytotoxicity. Ligation of activating NK receptors with their ligands expressed on target cells induces receptor clustering and actin reorganization at the interface and triggers polarized movement of lytic granules to the contact site. Although activation of the small GTPase Rac has been implicated in NK cell-mediated cytotoxicity, its precise role and the upstream regulator remain elusive. Here, we show that DOCK2, an atypical guanine nucleotide exchange factor for Rac, plays a key role in NK cell-mediated cytotoxicity. We found that although DOCK2 deficiency in NK cells did not affect conjugate formation with target cells, DOCK2-deficienct NK cells failed to effectively kill leukemia cells in vitro and major histocompatibility complex class I-deficient bone marrow cells in vivo, regardless of the sorts of activating receptors. In DOCK2-deficient NK cells, NKG2D-mediated Rac activation was almost completely lost, resulting in a severe defect in the lytic synapse formation. Similar results were obtained when the Rac guanine nucleotide exchange factor activity of DOCK2 was selectively abrogated. These results indicate that DOCK2-Rac axis controls NK cell-mediated cytotoxicity through the lytic synapse formation. (Blood. 2013;122(3):386-393) Introduction Natural killer (NK) cells are lymphocytes of the innate immune system that play an important role in protective immunity against viral infection and tumor progression but also contribute to rejection of bone marrow (BM) grafts via contact-dependent cytotoxicity.1,2 Activation of NK cells is regulated by a balance of activating and inhibitory signals delivered through the germ-line-encoded receptors that recognize ligands expressed on the surface of target cells.1,2 NK cells express multiple activating receptors including NKG2D, Ly49D, and the low-affinity receptor for immunoglobulin G (IgG), FcgRIIIa. 3 NKG2D recognizes endogenous major histocompatibility complex (MHC) class I-related molecules such as Rae1a-Rae1e, which were originally identified as retinoic acid-inducible proteins but were expressed at high levels primarily in virally infected cells and tumor cells. 4 On the other hand, Ly49D triggers the killing of Chinese hamster ovary (CHO) cells by recognizing hamster MHC class I molecules, 5 and FcgRIIIa is involved in antibody-dependent cell-mediated cytotoxicity (ADCC).1,2 Because these receptors lack cytoplasmic signaling elements, the delivery of activating signal is mediated through the associating transmembrane protein, such as DAP12, FcRg, CD3z, and DAP10, ...

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The requirement for NKG2D in NK cell–mediated rejection of parental bone marrow grafts is determined by MHC class I expressed by the graft recipient

Cited by 23 publications

References 35 publications

NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT

NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT

Natural Killer Group 2, Member D/NKG2D Ligands in Hematopoietic Cell Transplantation

The Rac activator DOCK2 regulates natural killer cell–mediated cytotoxicity in mice through the lytic synapse formation

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