CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adult mice

Noda, Mamiko; Omatsu, Yoshiki; Sugiyama, Tatsuki; Oishi, Shinya; Fujii, Nobutaka; Nagasawa, Takashi

doi:10.1182/blood-2010-04-277897

Cited by 114 publications

(91 citation statements)

References 44 publications

(54 reference statements)

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“…Genes up regulated in C14R NK cells were associated with the mitochondrion and cell differentiation, while genes involved in protein processing in the endoplasmic reticulum, transcriptional regulators and cellular organization were downregulated (Figure 5D and E). However, genes such as Cxcr3 and Cxcr4 , both of which are essential for infiltration and function of NK cells, 30–32 and the transcriptional regulator Nab2 were upregulated in Ly5.1 C14R . We observed that in Ly5.1 C14R mice, the number of NK cells found in the lung were enriched ~2.1 fold indicating that the failure of tumor control was not driven by the inability to migrate to the lung.…”

Section: Resultsmentioning

confidence: 97%

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

et al. 2018

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NKp46 (CD335) is a surface receptor shared by both human and mouse natural killer (NK) cells and innate lymphoid cells (ILCs) that transduces activating signals necessary to eliminate virus-infected cells and tumors. Here, we describe a spontaneous point mutation of cysteine to arginine (C14R) in the signal peptide of the NKp46 protein in congenic Ly5.1 mice and the newly generated NCRB6C14R strain. Ly5.1C14R NK cells expressed similar levels of Ncr1 mRNA as C57BL/6, but showed impaired surface NKp46 and reduced ability to control melanoma tumors in vivo. Expression of the mutant NKp46C14R in 293T cells showed that NKp46 protein trafficking to the cell surface was compromised. Although Ly5.1C14R mice had normal number of NK cells, they showed an increased number of early maturation stage NK cells. CD49a+ILC1s were also increased but these cells lacked the expression of TRAIL. ILC3s that expressed NKp46 were not detectable and were not apparent when examined by T-bet expression. Thus, the C14R mutation reveals that NKp46 is important for NK cell and ILC differentiation, maturation and function.SignificanceInnate lymphoid cells (ILCs) play important roles in immune protection. Various subsets of ILCs express the activating receptor NKp46 which is capable of recognizing pathogen derived and tumor ligands and is necessary for immune protection. Here, we describe a spontaneous point mutation in the signal peptide of the NKp46 protein in congenic Ly5.1 mice which are widely used for tracking cells in vivo. This Ncr1 C14R mutation impairs NKp46 surface expression resulting in destabilization of Ncr1 and accumulation of NKp46 in the endoplasmic reticulum. Loss of stable NKp46 expression impaired the maturation of NKp46+ ILCs and altered the expression of TRAIL and T-bet in ILC1 and ILC3, respectively.

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Section: Resultsmentioning

confidence: 97%

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

et al. 2018

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“…CXCL12 is required for NK development in addition to recruitment, suggesting that the high CXCL12 levels in the decidual environment might contribute to the unique phenotype and function of dNK cells. 80 Our unpublished data indeed demonstrate that trophoblasts instruct NK cell phenotype and function via CXCL12/CXCR4 signalling. Additionally, CCL2 secreted by DSC inhibits NK cells cytotoxicity by upregulation of SOCS3.…”

Section: Chemokine Instruction To Decidual Immune Cellsmentioning

confidence: 97%

The integrative roles of chemokines at the maternal–fetal interface in early pregnancy

2014

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Embryos express paternal antigens that are foreign to the mother, but the mother provides a special immune milieu at the fetal-maternal interface to permit rather than reject the embryo growth in the uterus until parturition by establishing precise crosstalk between the mother and the fetus. There are unanswered questions in the maintenance of pregnancy, including the poorly understood phenomenon of maternal tolerance to the allogeneic conceptus, and the remarkable biological roles of placental trophoblasts that invade the uterine wall. Chemokines are multifunctional molecules initially described as having a role in leukocyte trafficking and later found to participate in developmental processes such as differentiation and directed migration. It is increasingly evident that the gestational uterine microenvironment is characterized, at least in part, by the differential expression and secretion of chemokines that induce selective trafficking of leukocyte subsets to the maternal-fetal interface and regulate multiple events that are closely associated with normal pregnancy. Here, we review the expression and function of chemokines and their receptors at the maternal-fetal interface, with a special focus on chemokine as a key component in trophoblast invasiveness and placental angiogenesis, recruitment and instruction of immune cells so as to form a fetus-supporting milieu during pregnancy. The chemokine network is also involved in pregnancy complications.

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“…They Correspondence: Dr. Sam K. P. Kung e-mail: Sam.Kung2@med.umanitoba.ca acquire specific chemokine surface receptors during development and maturation [2,[10][11][12][13][14][15]. Chemokine receptors such as CCR7, CCR5, and CXCR3 are involved in the preferential migrations and localization of NK cells into the LNs [8,[16][17][18][19], whereas NK cells reside in blood, liver, and spleen exhibit higher CXCR1 and CX 3 CR1 expression [8,9,[20][21][22][23][24][25]. Nonchemokine family proteins such as chemerin and SIP 5 are also involved in the regulation of NK-cell trafficking [26,27].…”

mentioning

confidence: 99%

Microfluidic‐based, live‐cell analysis allows assessment of NK‐cell migration in response to crosstalk with dendritic cells

et al. 2014

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Migration and localization of NK cells into peripheral tissues are tightly regulated under normal and pathological conditions. The physiological importance of NK cell-DC crosstalk has been well documented. However, the ways in which DCs regulate the migratory properties of NK cells (such as chemotaxis, chemokinesis, chemo-repulsion) are not fully defined in vitro. Here, we employed a microfluidic platform to examine, at the single-cell level, C57BL/6 NK-cell migrations in a stable chemical gradient. We observed that soluble factors released by the immature and LPS-activated mature DCs induced a high level of chemotactic movement of IL-2-activated NK cells in vitro. We confirmed these findings in a standard trans-well migration assay, and identified CXCR3 as a key receptor on the NK cells that mediated the migration. More interestingly, we revealed a novel function of granulocyte macrophage colony-stimulating factor in repulsing NK-cell migrations. The future uses of such microfluidic device in the systematic evaluations of NK-cell migratory responses in NK cell-DC crosstalk will provide new insights into the development of DC-based NK-cell therapies against tumor and infections.Keywords: Bone marrow-derived dendritic cells r Chemo-repulsion r Chemotaxis r Microfluidic device r Natural killer cell r NK-DC crosstalk Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction NK cells are motile bone marrow (BM)-derived lymphocytes that play a key role in innate immunity against viral, microbial infections, and transformed cells [1][2][3]. They are capable of killing transformed or infected cells [1,2,4,5], and/or producing cytokines/chemokines that can profoundly influence the quality and magnitude of the adaptive immune responses [6][7][8][9]. They Correspondence: Dr. Sam K. P. Kung e-mail: Sam.Kung2@med.umanitoba.ca acquire specific chemokine surface receptors during development and maturation [2,[10][11][12][13][14][15]. Chemokine receptors such as CCR7, CCR5, and CXCR3 are involved in the preferential migrations and localization of NK cells into the LNs [8,[16][17][18][19], whereas NK cells reside in blood, liver, and spleen exhibit higher CXCR1 and CX 3 CR1 expression [8,9,[20][21][22][23][24][25]. Nonchemokine family proteins such as chemerin and SIP 5 are also involved in the regulation of NK-cell trafficking [26,27]. Collectively, they highlight the complexity of the environmental regulation of NK-cell migrations in physiological and pathological conditions. NK-cell activation and functions are regulated by cytokine/ chemokine and/or DC in the microenvironments [18,[28][29][30] [36,37]. In this report, we demonstrated an application of such microfluidic device in examining how soluble factors produced by DC regulated NK-cell migrations in vitro. Results A microfluidic platform to perform live-cell imaging of NK-cell migrationsWe used the established Y-shaped microfluidic device to examine chemotactic or chemo-repulsive movements of NK cells ...

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CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adult mice

Cited by 114 publications

References 44 publications

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

The integrative roles of chemokines at the maternal–fetal interface in early pregnancy

Microfluidic‐based, live‐cell analysis allows assessment of NK‐cell migration in response to crosstalk with dendritic cells

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