Bone Marrow Allograft Rejection Mediated by a Novel Murine NK Receptor, NKG2I

Natural killer (NK) cells mediate bone marrow allograft rejection. However, the molecular mechanisms underlying such a rejection remain elusive. In previous analyses, it has been shown that NK cells recognize allogeneic target cells through Ly-49s and CD94/NKG2 heterodimers. Here, we describe identification and characterization of a novel murine NK receptor, NKG2I, belonging to the NKG2 family. NKG2I, which was composed of 226 amino acids, showed ∼40% homology to the murine NKG2D and CD94 in the C-type lectin domain. Flow cytometric analysis with anti-NKG2I monoclonal antibody (mAb) revealed that expression of NKG2I was largely confined to NK and NKT cells, but was not seen in T cells. Furthermore, anti-NKG2I mAb inhibited NK cell–mediated cytotoxicity, whereas cross-linking of NKG2I enhanced interleukin 2– and interleukin 12–dependent interferon-γ production. Similarly, the injection of anti-NKG2I mAb before the allogeneic bone marrow transfer in vivo impinged on the function of NKG2I, resulting in the enhanced colony formation in the spleen. NKG2I is a novel activating receptor mediating recognition and rejection of allogeneic target cells.

Download Full-text

Role of a NK receptor, KLRE-1, in bone marrow allograft rejection: analysis with KLRE-1–deficient mice

Blood ◽

10.1182/blood-2003-10-3468 ◽

2004 ◽

Vol 104 (3) ◽

pp. 781-783 ◽

Cited By ~ 7

Author(s):

Eiko Shimizu ◽

Junzo Koike ◽

Hiroshi Wakao ◽

Ken-ichiro Seino ◽

Haruhiko Koseki ◽

...

Keyword(s):

Bone Marrow ◽

Allograft Rejection ◽

Colony Formation ◽

Target Cells ◽

Host Immune System ◽

Allogeneic Bone ◽

Wild Type ◽

Deficient Mice ◽

Nk Receptor

AbstractNatural killer (NK) cells play a pivotal role in the immune reaction during the bone marrow allograft rejection. Little is known, however, about the molecular mechanisms underlying the NK cell–mediated allograft recognition and rejection. In this report, we assessed the role of a recently identified NK receptor, killer cell lectinlike receptor 1 (KLRE-1), by generating knock-out mice. KLRE-1–deficient mice were born at an expected frequency and showed no aberrant phenotype on growth and lymphoid development. Nevertheless, KLRE-1–deficient cells showed a severely compromised allogeneic cytotoxic activity compared with the wild-type cells. Furthermore, allogeneic bone marrow transfer culminated in colony formation in the spleen of KLRE-1–deficient mice, whereas no colony formation was observed in wild-type recipient mice. These results demonstrate that KLRE-1 is a receptor mediating recognition and rejection of allogeneic target cells in the host immune system.

Download Full-text

Impaired natural and CD16-mediated NK cell cytotoxicity in patients with WAS and XLT: ability of IL-2 to correct NK cell functional defect

Blood ◽

10.1182/blood-2003-07-2621 ◽

2004 ◽

Vol 104 (2) ◽

pp. 436-443 ◽

Cited By ~ 102

Author(s):

Angela Gismondi ◽

Loredana Cifaldi ◽

Cinzia Mazza ◽

Silvia Giliani ◽

Silvia Parolini ◽

...

Keyword(s):

Nk Cells ◽

Molecular Mechanisms ◽

Nk Cell ◽

Interleukin 2 ◽

Target Cells ◽

Cell Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Functional Defect ◽

Nk Cell Cytotoxicity ◽

Syndrome Protein

Abstract In this study we show that Wiskott-Aldrich syndrome protein (WASp), a critical regulator of actin cytoskeleton that belongs to the Scar/WAVE family, plays a crucial role in the control of natural killer (NK) cell cytotoxicity. Analysis of NK cell numbers and cytotoxic activity in patients carrying different mutations in the WASP coding gene indicated that although the percentage of NK cells was normal or increased, natural cytotoxicity and antibody-mediated NK cell cytotoxicity were inhibited in all patients with the classical WAS phenotype and in most patients carrying mutations associated with the X-linked thrombocytopenia (XLT) phenotype. The inhibition of NK cell-mediated cytotoxicity was associated with the reduced ability of WAS and XLT NK cells to form conjugates with susceptible target cells and to accumulate F-actin on binding. Treatment with interleukin-2 (IL-2) corrected the functional defects of NK cells by affecting their ability to bind to sensitive target cells and to accumulate F-actin. In addition, we provide information on the molecular mechanisms that control WASp function, demonstrating that binding of NK cells to sensitive targets or triggering through CD16 by means of reverse antibody-dependent cellular cytotoxicity (ADCC) rapidly activates Cdc42. We also found that WASp undergoes tyrosine phosphorylation upon CD16 or β2-integrin engagement on NK cells. (Blood. 2004;104:436-443)

Download Full-text

Interleukin-2 enhances the response of natural killer cells to interleukin-12 through up-regulation of the interleukin-12 receptor and STAT4

Blood ◽

10.1182/blood.v95.10.3183.010k36_3183_3190 ◽

2000 ◽

Vol 95 (10) ◽

pp. 3183-3190 ◽

Cited By ~ 4

Author(s):

Kathy S. Wang ◽

David A. Frank ◽

Jerome Ritz

Keyword(s):

T Lymphocytes ◽

Nk Cells ◽

Natural Killer ◽

Critical Role ◽

Interleukin 2 ◽

Interleukin 12 ◽

Target Cells ◽

Functional Responses ◽

Antitumor Effects ◽

Ifn Γ

Interleukin (IL)-12 plays a critical role in modulating the activities of natural killer (NK) cells and T lymphocytes. In animal models, IL-12 has potent antitumor effects that are likely mediated by its ability to enhance the cytotoxic activity of NK cells and cytotoxic T lymphocytes, and to induce the production of interferon (IFN)-γ by NK and T cells. In addition to IL-12, NK cells are responsive to IL-2, and may mediate some of the antitumor effects of IL-2. In this study, we examine the interaction between IL-2 and the signaling events induced by IL-12 in NK cells. We find that IL-2 not only up-regulates the expression of IL-12Rβ1 and IL-12Rβ2, it also plays an important role in up-regulating and maintaining the expression of STAT4, a critical STAT protein involved in IL-12 signaling in NK cells. In contrast to the effects of IL-2 alone, expression of IL-12 receptors and STAT4 are unaffected or decreased by IL-12 or the combination of IL-2 and IL-12. Through expression of high levels of IL-12 receptors and STAT4, IL-2–primed NK cells show enhanced functional responses to IL-12 as measured by IFN-γ production and the killing of target cells. NK cells from cancer patients who received low-dose IL-2 treatment also exhibited increased expression of IL-12 receptor chains, suggesting that IL-2 may enhance the response to IL-12 in vivo. These findings provide a molecular framework to understand the interaction between IL-2 and IL-12 in NK cells, and suggest strategies for improving the effectiveness of these cytokines in the immunotherapy of cancer.

Download Full-text

Activated natural killer cells and interleukin-2 promote granulocytic and megakaryocytic reconstitution after syngeneic bone marrow transplantation in mice

Blood ◽

10.1182/blood.v82.8.2577.bloodjournal8282577 ◽

1993 ◽

Vol 82 (8) ◽

pp. 2577-2584

Author(s):

AK Siefer ◽

DL Longo ◽

CL Harrison ◽

CW Reynolds ◽

WJ Murphy

Keyword(s):

Bone Marrow ◽

Nk Cells ◽

Natural Killer ◽

Bone Marrow Cells ◽

Interleukin 2 ◽

Flow Cytometric Analysis ◽

Severe Combined Immune Deficiency ◽

Cell Counts ◽

Hematopoietic Reconstitution

Purified populations of natural killer (NK) cells were obtained from mice with severe combined immune deficiency (SCID). SCID spleen cells were cultured and activated with recombinant human interleukin-2 (rhIL- 2) in vitro. The activated NK cells were then transferred with syngeneic BALB/c bone marrow cells (BMC) and rhIL-2 into lethally irradiated syngeneic recipients to determine their effect on long-term hematopoietic reconstitution. On analysis, the transfer of rhIL-2- activated NK cells along with BMC resulted in significant increases in splenic and BM hematopoietic progenitor cells when compared with those for mice not receiving NK cells. Histologic and flow cytometric analysis showed a marked increase in granulocytic and megakaryocytic lineage cells present in the spleens of the mice receiving activated NK cells. Analysis of the peripheral blood indicated that the transfer of activated NK cells with BMC also significantly improved platelet and total white blood cell counts, with increases in segmented neutrophils. Erythroid recovery was not affected. Finally, lethally irradiated mice receiving activated NK cells and rhIL-2 along with limiting numbers of syngeneic BMC showed a marked increase in survival rate. These results show that the use of populations enriched for activated NK cells after syngeneic BM transplantation (BMT) has a profound enhancing effect on engraftment primarily affecting megakaryocytic and granulocytic cell reconstitution. Therefore, the transfer of activated NK cells and rhIL- 2 may be of clinical use to promote hematopoietic reconstitution after BMT.

Download Full-text

The Target Cells for Rat NK Cells among Allogeneic Bone Marrow Cells

Advances in Experimental Medicine and Biology - Histophysiology of the Immune System ◽

10.1007/978-1-4684-5535-9_67 ◽

1988 ◽

pp. 439-445 ◽

Cited By ~ 1

Author(s):

B. Rolstad ◽

S. Fossum ◽

H. B. Benestad

Keyword(s):

Bone Marrow ◽

Nk Cells ◽

Bone Marrow Cells ◽

Allogeneic Bone Marrow ◽

Target Cells ◽

Allogeneic Bone ◽

Marrow Cells

Download Full-text

Interleukin-2 enhances the response of natural killer cells to interleukin-12 through up-regulation of the interleukin-12 receptor and STAT4

Blood ◽

10.1182/blood.v95.10.3183 ◽

2000 ◽

Vol 95 (10) ◽

pp. 3183-3190 ◽

Cited By ~ 113

Author(s):

Kathy S. Wang ◽

David A. Frank ◽

Jerome Ritz

Keyword(s):

T Lymphocytes ◽

Nk Cells ◽

Natural Killer ◽

Critical Role ◽

Interleukin 2 ◽

Interleukin 12 ◽

Target Cells ◽

Functional Responses ◽

Antitumor Effects ◽

Ifn Γ

Abstract Interleukin (IL)-12 plays a critical role in modulating the activities of natural killer (NK) cells and T lymphocytes. In animal models, IL-12 has potent antitumor effects that are likely mediated by its ability to enhance the cytotoxic activity of NK cells and cytotoxic T lymphocytes, and to induce the production of interferon (IFN)-γ by NK and T cells. In addition to IL-12, NK cells are responsive to IL-2, and may mediate some of the antitumor effects of IL-2. In this study, we examine the interaction between IL-2 and the signaling events induced by IL-12 in NK cells. We find that IL-2 not only up-regulates the expression of IL-12Rβ1 and IL-12Rβ2, it also plays an important role in up-regulating and maintaining the expression of STAT4, a critical STAT protein involved in IL-12 signaling in NK cells. In contrast to the effects of IL-2 alone, expression of IL-12 receptors and STAT4 are unaffected or decreased by IL-12 or the combination of IL-2 and IL-12. Through expression of high levels of IL-12 receptors and STAT4, IL-2–primed NK cells show enhanced functional responses to IL-12 as measured by IFN-γ production and the killing of target cells. NK cells from cancer patients who received low-dose IL-2 treatment also exhibited increased expression of IL-12 receptor chains, suggesting that IL-2 may enhance the response to IL-12 in vivo. These findings provide a molecular framework to understand the interaction between IL-2 and IL-12 in NK cells, and suggest strategies for improving the effectiveness of these cytokines in the immunotherapy of cancer.

Download Full-text

Activated natural killer cells and interleukin-2 promote granulocytic and megakaryocytic reconstitution after syngeneic bone marrow transplantation in mice

Blood ◽

10.1182/blood.v82.8.2577.2577 ◽

1993 ◽

Vol 82 (8) ◽

pp. 2577-2584 ◽

Cited By ~ 16

Author(s):

AK Siefer ◽

DL Longo ◽

CL Harrison ◽

CW Reynolds ◽

WJ Murphy

Keyword(s):

Bone Marrow ◽

Nk Cells ◽

Natural Killer ◽

Bone Marrow Cells ◽

Interleukin 2 ◽

Flow Cytometric Analysis ◽

Severe Combined Immune Deficiency ◽

Cell Counts ◽

Hematopoietic Reconstitution

Abstract Purified populations of natural killer (NK) cells were obtained from mice with severe combined immune deficiency (SCID). SCID spleen cells were cultured and activated with recombinant human interleukin-2 (rhIL- 2) in vitro. The activated NK cells were then transferred with syngeneic BALB/c bone marrow cells (BMC) and rhIL-2 into lethally irradiated syngeneic recipients to determine their effect on long-term hematopoietic reconstitution. On analysis, the transfer of rhIL-2- activated NK cells along with BMC resulted in significant increases in splenic and BM hematopoietic progenitor cells when compared with those for mice not receiving NK cells. Histologic and flow cytometric analysis showed a marked increase in granulocytic and megakaryocytic lineage cells present in the spleens of the mice receiving activated NK cells. Analysis of the peripheral blood indicated that the transfer of activated NK cells with BMC also significantly improved platelet and total white blood cell counts, with increases in segmented neutrophils. Erythroid recovery was not affected. Finally, lethally irradiated mice receiving activated NK cells and rhIL-2 along with limiting numbers of syngeneic BMC showed a marked increase in survival rate. These results show that the use of populations enriched for activated NK cells after syngeneic BM transplantation (BMT) has a profound enhancing effect on engraftment primarily affecting megakaryocytic and granulocytic cell reconstitution. Therefore, the transfer of activated NK cells and rhIL- 2 may be of clinical use to promote hematopoietic reconstitution after BMT.

Download Full-text

CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset

Blood ◽

10.1182/blood-2010-04-282301 ◽

2010 ◽

Vol 116 (19) ◽

pp. 3865-3874 ◽

Cited By ~ 392

Author(s):

Sandra Lopez-Vergès ◽

Jeffrey M. Milush ◽

Suchitra Pandey ◽

Vanessa A. York ◽

Janice Arakawa-Hoyt ◽

...

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Interleukin 2 ◽

Cell Subset ◽

Interferon Γ ◽

Distinct Pattern ◽

Interleukin 12 ◽

Target Cells ◽

Functional Differences ◽

Higher Sensitivity

Abstract Natural killer (NK) cells are innate immune lymphocytes that express a heterogeneous repertoire of germline-encoded receptors and undergo a distinct pattern of maturation. CD57 is a marker of terminal differentiation on human CD8+ T cells. Very few newborn or fetal NK cells express CD57; however, the frequency of CD57-bearing NK cells increases with age. We assessed the transcriptional, phenotypic, and functional differences between CD57+ and CD57− NK cells within the CD56dim mature NK subset. CD57+ NK cells express a repertoire of NK-cell receptors, suggestive of a more mature phenotype, and proliferate less when stimulated with target cells and/or cytokines. By contrast, a higher frequency of CD57+ NK cells produced interferon-γ and demonstrated more potent lytic activity when these cells were stimulated through the activating receptor CD16; however, they are less responsive to stimulation by interleukin-12 and interleukin-18. Finally, CD57 expression is induced on CD57−CD56dim NK cells after activation by interleukin-2. A combination of a mature phenotype, a higher cytotoxic capacity, a higher sensitivity to stimulation via CD16, with a decreased responsiveness to cytokines, and a decreased capacity to proliferate suggest that CD57+ NK cells are highly mature and might be terminally differentiated.

Download Full-text