scholarly journals Engraftment of Bone Marrow from Severe Combined Immunodeficient (SCID) Mice Reverses the Reproductive Deficits in Natural Killer Cell–deficient tgε26 Mice

1998 ◽  
Vol 187 (2) ◽  
pp. 217-223 ◽  
Author(s):  
Marie-Josée Guimond ◽  
Baoping Wang ◽  
B. Anne Croy
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Fetal Loss ◽  
Vascular Pathology ◽  
Metrial Gland ◽  
Unk Cell

A large, transient population of natural killer (NK) cells appears in the murine uterine mesometrial triangle during pregnancy. Depletion of uterine (u) NK cells, recently achieved using gene-ablated and transgenic mice, results in pathology. Pregnancies from matings of homozygous NK and T cell–deficient tgε26 mice have <1% of normal uNK cell frequency, no development of an implantation site–associated metrial gland, and an edematous decidua with vascular pathology that includes abnormally high vessel walls/lumens ratios. Fetal loss of 64% occurs midgestation and placentae are small. None of these features are seen in pregnant T cell–deficient mice. To confirm the role of the NK cell deficiency in these reproductive deficits, transplantation of tgε26 females was undertaken using bone marrow from B and T cell–deficient scid/scid donors. Engrafted pregnant females have restoration of the uNK cell population, induced metrial gland differentiation, reduced anomalies in the decidua and decidual blood vessels, increased placental sizes, and restoration of fetal viability at all gestational days studied (days 10, 12, and 14). Thus, uNK cells appear to have critical functions in pregnancy that promote decidual health, the appropriate vascularization of implantation sites, and placental size.

scholarly journals Hematopoietic cells and radioresistant host elements influence natural killer cell differentiation.

1993 ◽  
Vol 178 (1) ◽  
pp. 223-229 ◽  
Author(s):  
M Sykes ◽  
M W Harty ◽  
F M Karlhofer ◽  
D A Pearson ◽  
G Szot ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Host Cells ◽  
Cell Repertoire ◽  
Clonal Deletion ◽  
Bone Marrow Derived Cells

Radioresistant host elements mediate positive selection of developing thymocytes, whereas bone marrow-derived cells induce clonal deletion of T cells with receptors that are strongly autoreactive. In contrast to T cell development, little is known about the elements governing the natural killer (NK) cell repertoire, which, similar to the T cell repertoire, differs between individuals bearing different major histocompatibility complex (MHC) phenotypes. We have used murine bone marrow transplantation models to analyze the influence of donor and host MHC on an NK cell subset. We examined the expression of Ly-49, which is strongly expressed on a subpopulation of NK cells of H-2b mice, but not by NK cells of H-2a mice, probably because of a negative effect induced by the interaction of Ly-49 with Dd. To evaluate the effect of hematopoietic cell H-2a expression on Ly-49 expression of H-2b NK cells, we prepared mixed allogeneic chimeras by administering T cell-depleted allogeneic (B10.A, H-2a) and host-type (B10, H-2b) marrow to lethally irradiated B10 mice, or by administering B10. A marrow to B10 recipients conditioned by a nonmyeloablative regimen. Expression of H-2a on bone marrow-derived cells was sufficient to downregulate Ly-49 expression on both H-2a and H-2b NK cells. This downregulation was thymus independent. To examine the effect of H-2a expressed only on radioresistant host elements, we prepared fully allogeneic chimeras by administering B10 bone marrow to lethally irradiated B10.A recipients. B10 NK cells of these fully allogeneic chimeras also showed downregulation of Ly-49 expression. The lower level of H-2a expressed on H-2b x H-2a F1 cells induced more marked downregulation of Ly-49 expression on B10 NK cells when presented on donor marrow in mixed chimeras than when expressed only on radioresistant host cells. Our studies show that differentiation of NK cells is determined by interactions with MHC molecules expressed on bone marrow-derived cells and, to a lesser extent, by MHC antigens expressed on radioresistant host elements.

scholarly journals CD94 1A transcripts characterize lymphoblastic lymphoma/leukemia of immature natural killer cell origin with distinct clinical features

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3567-3574 ◽  
Author(s):  
Chung-Wu Lin ◽  
Ting-Yun Liu ◽  
Shee-Uan Chen ◽  
Kun-Teng Wang ◽  
L. Jeffrey Medeiros ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Lineage ◽  
Lymphoid Cells ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Gene Rearrangements

AbstractMost lymphoblastic lymphomas (LBLs) are regarded as neoplasms of immature T cells because they express cytoplasmic CD3 and frequently carry T-cell receptor (TCR) gene rearrangements. Immature natural killer (NK) and T cells, however, have a common bipotent T/NK-cell precursor in the thymus, and NK cells also express cytoplasmic CD3. Thus, some LBLs could arise from immature NK cells. Mature NK cells express 2 CD94 transcripts: 1A, induced by interleukin 15 (IL-15), and 1B constitutively. Because immature NK cells require IL-15 for development, CD94 1A transcripts could be a marker of NK-LBL. To test this hypothesis, we used laser capture microdissection to isolate IL-15 receptor α+ lymphoid cells from the thymus and showed that these cells contained CD94 1A transcripts. We then assessed for CD94 transcripts in 21 cases of LBL that were cytoplasmic CD3+, nuclear terminal deoxynucleotidyl transferase positive (TdT+), and CD56-, consistent with either the T-cell or NK-cell lineage. We found that 7 LBLs expressed CD94 1A transcripts without TCR gene rearrangements, suggesting NK-cell lineage. Patients with NK-LBL were younger than patients with T-LBL (15 years versus 33 years; P = .11) and had a better 2-year survival (100% versus 27%; P < .01). These results improve the current classification of LBL and contribute to our understanding of NK-cell differentiation.

scholarly journals HIV modulates the expression of ligands important in triggering natural killer cell cytotoxic responses on infected primary T-cell blasts

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1207-1214 ◽  
Author(s):  
Jeffrey Ward ◽  
Matthew Bonaparte ◽  
Jennifer Sacks ◽  
Jacqueline Guterman ◽  
Manuela Fogli ◽  
...  
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Target Cells ◽  
Nk Cell Receptors ◽  
Infected Cells ◽  
Cytotoxic Responses

AbstractThe ability of natural killer (NK) cells to kill virus-infected cells depends on the presence of ligands for activation receptors on the target cells. We found the presence of few, if any, NKp30 and NK46 ligands on T cell blasts infected with HIV, although NKp44 ligands were found on infected cells. HIV does induce the NKG2D ligands ULBP-1, -2, and -3. These ligands are involved in triggering NK cells to kill autologous HIV-infected cells, because interfering with the interaction between NKG2D, but not NKp46, on NK cells and its ligands on HIV-infected cells drastically reduced the lysis of infected cells. Interfering with the binding of the NK-cell coreceptors NTB-A and 2B4 to their ligands also decreased destruction by NK cells. The coreceptor ligands, NTB-A and CD48, were also found to be down-regulated during the course of HIV infection. Thus, ligands for NK-cell receptors are modulated during the course of HIV infection, which may greatly alter NK cells' ability to kill the infected cells.

scholarly journals T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow

2014 ◽  
Vol 211 (3) ◽  
pp. 563-577 ◽  
Author(s):  
Cécile Daussy ◽  
Fabrice Faure ◽  
Katia Mayol ◽  
Sébastien Viel ◽  
Georg Gasteiger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Fetal Liver ◽  
Killer Cell ◽  
Ectopic Expression ◽  
Nkt Cells ◽  
Lymphoid Cells ◽  
Cell Lineages

Trail+DX5−Eomes− natural killer (NK) cells arise in the mouse fetal liver and persist in the adult liver. Their relationships with Trail−DX5+ NK cells remain controversial. We generated a novel Eomes-GFP reporter murine model to address this question. We found that Eomes− NK cells are not precursors of classical Eomes+ NK cells but rather constitute a distinct lineage of innate lymphoid cells. Eomes− NK cells are strictly dependent on both T-bet and IL-15, similarly to NKT cells. We observed that, in the liver, expression of T-bet in progenitors represses Eomes expression and the development of Eomes+ NK cells. Reciprocally, the bone marrow (BM) microenvironment restricts T-bet expression in developing NK cells. Ectopic expression of T-bet forces the development of Eomes− NK cells, demonstrating that repression of T-bet is essential for the development of Eomes+ NK cells. Gene profile analyses show that Eomes− NK cells share part of their transcriptional program with NKT cells, including genes involved in liver homing and NK cell receptors. Moreover, Eomes− NK cells produce a broad range of cytokines, including IL-2 and TNF in vitro and in vivo, during immune responses against vaccinia virus. Thus, mutually exclusive expression of T-bet and Eomes drives the development of different NK cell lineages with complementary functions.

scholarly journals Identification of the earliest natural killer cell–committed progenitor in murine bone marrow

Blood ◽  
2011 ◽  
Vol 118 (20) ◽  
pp. 5439-5447 ◽  
Author(s):  
John W. Fathman ◽  
Deepta Bhattacharya ◽  
Matthew A. Inlay ◽  
Jun Seita ◽  
Holger Karsunky ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Fate ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Lineage Commitment ◽  
Color Flow ◽  
Cell Commitment

Abstract Natural killer (NK) cells develop in the bone marrow and are known to gradually acquire the ability to eliminate infected and malignant cells, yet the cellular stages of NK lineage commitment and maturation are incompletely understood. Using 12-color flow cytometry, we identified a novel NK-committed progenitor (pre-NKP) that is a developmental intermediate between the upstream common lymphoid progenitor and the downstream NKP, previously assumed to represent the first stage of NK lineage commitment. Our analysis also refined the purity of NKPs (rNKP) by 6-fold such that 50% of both pre-NKP and rNKP cells gave rise to NKp46+ NK cells at the single-cell level. On transplantation into unconditioned Rag2−/−Il2rγc−/− recipients, both pre-NKPs and rNKPs generated mature NK cells expressing a repertoire of Ly49 family members that degranulated on stimulation ex vivo. Intrathymic injection of these progenitors, however, yielded no NK cells, suggesting a separate origin of thymic NK cells. Unlike the rNKP, the pre-NKP does not express IL-2Rβ (CD122), yet it is lineage committed toward the NK cell fate, adding support to the theory that IL-15 signaling is not required for NK commitment. Taken together, our data provide a high-resolution in vivo analysis of the earliest steps of NK cell commitment and maturation.

scholarly journals Natural killer cell behavior in lymph nodes revealed by static and real-time imaging

2006 ◽  
Vol 203 (3) ◽  
pp. 619-631 ◽  
Author(s):  
Marc Bajénoff ◽  
Béatrice Breart ◽  
Alex Y.C. Huang ◽  
Hai Qi ◽  
Julie Cazareth ◽  
...  
Keyword(s):  
T Cell ◽  
Lymph Nodes ◽  
Nk Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Leishmania Major ◽  
Nk Cell ◽  
Killer Cell

Natural killer (NK) cells promote dendritic cell (DC) maturation and influence T cell differentiation in vitro. To better understand the nature of the putative interactions among these cells in vivo during the early phases of an adaptive immune response, we have used immunohistochemical analysis and dynamic intravital imaging to study NK cell localization and behavior in lymph nodes (LNs) in the steady state and shortly after infection with Leishmania major. In the LNs of naive mice, NK cells reside in the medulla and the paracortex, where they closely associate with DCs. In contrast to T cells, intravital microscopy revealed that NK cells in the superficial regions of LNs were slowly motile and maintained their interactions with DCs over extended times in the presence or absence of immune-activating signals. L. major induced NK cells to secrete interferon-γ and to be recruited to the paracortex, where concomitant CD4 T cell activation occurred. Therefore, NK cells form a reactive but low mobile network in a strategic area of the LN where they can receive inflammatory signals, interact with DCs, and regulate colocalized T cell responses.

scholarly journals Tumor growth impedes natural-killer-cell maturation in the bone marrow

Blood ◽  
2006 ◽  
Vol 108 (1) ◽  
pp. 246-252 ◽  
Author(s):  
John O. Richards ◽  
Xing Chang ◽  
Bradley W. Blaser ◽  
Michael A. Caligiuri ◽  
Pan Zheng ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Growth ◽  
Nk Cells ◽  
Natural Killer ◽  
Bone Marrow Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Development ◽  
Functional Maturation ◽  
Ifn Γ

Natural-killer (NK)-cell dysfunction and IFN-γ deficiencies have been associated with increased incidence of both malignancy and infection. The immunologic basis of NK-cell defects in cancer-bearing hosts has not been extensively studied. Here, we demonstrate that multiple lineages of tumors, including thymoma, breast cancer, colon cancer, and melanoma cell lines, interrupt functional maturation during NK-cell development in the bone marrow. The immature NK cells in the periphery of tumor-bearing mice had impaired IFN-γ production but seemingly normal cytotoxicity. T cells are not involved in this NK maturation arrest, because T-cell depletion did not restore NK-cell development. Moreover, the extent of tumor-cell infiltration into the bone marrow does not correlate with defective NK maturation. Interestingly, the defect was associated with a significant reduction in the IL-15Rα+ cells in the non-T, non-NK compartment of bone marrow cells and restored by overexpression of IL-15. Our data demonstrate that tumor growth can impede functional maturation of NK cells, most likely by interrupting the requisite IL-15 signaling pathway. (Blood. 2006;108:246-252)

scholarly journals Natural Killer Cell–Mediated Eradication of Neuroblastoma Metastases to Bone Marrow by Targeted Interleukin-2 Therapy

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1706-1715 ◽  
Author(s):  
Holger N. Lode ◽  
Rong Xiang ◽  
Torsten Dreier ◽  
Nissi M. Varki ◽  
Stephen D. Gillies ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Fusion Protein ◽  
Nk Cells ◽  
Natural Killer ◽  
Therapeutic Effect ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Interleukin 2

Targeted interleukin-2 (IL-2) therapy with a genetically engineered antidisialoganglioside GD2 antibody–IL-2 fusion protein induced a cell-mediated antitumor response that effectively eradicated established bone marrow and liver metastases in a syngeneic model of neuroblastoma. The mechanism involved is exclusively natural killer (NK) cell–dependent, because NK-cell deficiency abrogated the antitumor effect. In contrast, the fusion protein remained completely effective in the T-cell–deficient mice or immunocompetent mice depleted of CD8+ T cells in vivo. A strong stimulation of NK-cell activity was also shown in vitro. Immunohistology of the leukocytic infiltrate of livers from treated mice revealed a strong staining for NK cells but not for CD8+ T cells. The therapeutic effect of the fusion protein was increased when combined with NK-cell–stimulating agents, such as poly I:C or recombinant mouse interferon-γ. In conclusion, these data show that targeted delivery of cytokines to the tumor microenvironment offers a new strategy to elicit an effective cellular immune response mediated by NK cells against metastatic neuroblastoma. This therapeutic effect may have general clinical implications for the treatment of patients with minimal residual disease who suffer from T-cell suppression after high-dose chemotherapy but are not deficient in NK cells.

scholarly journals Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity

Blood ◽  
2012 ◽  
Vol 119 (16) ◽  
pp. 3734-3743 ◽  
Author(s):  
Lishomwa C. Ndhlovu ◽  
Sandra Lopez-Vergès ◽  
Jason D. Barbour ◽  
R. Brad Jones ◽  
Aashish R. Jha ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Subset ◽  
Target Cells ◽  
Type I ◽  
Human Natural Killer Cell ◽  
Cell Responses

Abstract Natural killer (NK) cells are innate lymphocytes that play an important role against viral infections and cancer. This effect is achieved through a complex mosaic of inhibitory and activating receptors expressed by NK cells that ultimately determine the magnitude of the NK-cell response. The T-cell immunoglobulin– and mucin domain–containing (Tim)–3 receptor was initially identified as a T-helper 1–specific type I membrane protein involved in regulating T-cell responses. Human NK cells transcribe the highest amounts of Tim-3 among lymphocytes. Tim-3 protein is expressed on essentially all mature CD56dimCD16+ NK cells and is expressed heterogeneously in the immature CD56brightCD16– NK-cell subset in blood from healthy adults and in cord blood. Tim-3 expression was induced on CD56brightCD16− NK cells after stimulation with IL-15 or IL-12 and IL-18 in vitro, suggesting that Tim-3 is a maturation marker on NK cells. Whereas Tim-3 has been used to identify dysfunctional T cells, NK cells expressing high amounts of Tim-3 are fully responsive with respect to cytokine production and cytotoxicity. However, when Tim-3 was cross-linked with antibodies it suppressed NK cell–mediated cytotoxicity. These findings suggest that NK-cell responses may be negatively regulated when NK cells encounter target cells expressing cognate ligands of Tim-3.

scholarly journals Natural Killer Cell–Mediated Eradication of Neuroblastoma Metastases to Bone Marrow by Targeted Interleukin-2 Therapy

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1706-1715 ◽  
Author(s):  
Holger N. Lode ◽  
Rong Xiang ◽  
Torsten Dreier ◽  
Nissi M. Varki ◽  
Stephen D. Gillies ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Fusion Protein ◽  
Nk Cells ◽  
Natural Killer ◽  
Therapeutic Effect ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Interleukin 2

Abstract Targeted interleukin-2 (IL-2) therapy with a genetically engineered antidisialoganglioside GD2 antibody–IL-2 fusion protein induced a cell-mediated antitumor response that effectively eradicated established bone marrow and liver metastases in a syngeneic model of neuroblastoma. The mechanism involved is exclusively natural killer (NK) cell–dependent, because NK-cell deficiency abrogated the antitumor effect. In contrast, the fusion protein remained completely effective in the T-cell–deficient mice or immunocompetent mice depleted of CD8+ T cells in vivo. A strong stimulation of NK-cell activity was also shown in vitro. Immunohistology of the leukocytic infiltrate of livers from treated mice revealed a strong staining for NK cells but not for CD8+ T cells. The therapeutic effect of the fusion protein was increased when combined with NK-cell–stimulating agents, such as poly I:C or recombinant mouse interferon-γ. In conclusion, these data show that targeted delivery of cytokines to the tumor microenvironment offers a new strategy to elicit an effective cellular immune response mediated by NK cells against metastatic neuroblastoma. This therapeutic effect may have general clinical implications for the treatment of patients with minimal residual disease who suffer from T-cell suppression after high-dose chemotherapy but are not deficient in NK cells.

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