Activating and Inhibitory Ly49 Receptors Modulate NK Cell Chemotaxis to CXC Chemokine Ligand (CXCL) 10 and CXCL12

Inngjerdingen, Marit; Rolstad, Bent; Ryan, James C.

doi:10.4049/jimmunol.171.6.2889

Cited by 30 publications

(33 citation statements)

References 45 publications

(41 reference statements)

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“…The lack of TYK2 does not inhibit invasion of NK/NKT cells into the evolving lymphoma, since the numbers of NK and NKT cells in TYK2 -/-lymphoma were comparable to those in WT controls. Infiltration of immune cells into tumors is controlled by chemokine receptors, which activate JAK-STAT signaling cascades (42,43). Accordingly, our observations exclude a role for TYK2 in tumor invasion.…”

Section: Discussionmentioning

confidence: 62%

TYK2 is a key regulator of the surveillance of B lymphoid tumors

Stoiber¹,

Kovacic²,

Schuster³

et al. 2004

J. Clin. Invest.

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Aberrant activation of the JAK-STAT pathway has been implicated in tumor formation; for example, constitutive activation of JAK2 kinase or the enforced expression of STAT5 induces leukemia in mice. We show here that the Janus kinase TYK2 serves an opposite function. Mice deficient in TYK2 developed Abelsoninduced B lymphoid leukemia/lymphoma as well as TEL-JAK2-induced T lymphoid leukemia with a higher incidence and shortened latency compared with WT controls. The cell-autonomous properties of Abelson murine leukemia virus-transformed (A-MuLV-transformed) TYK2 -/-cells were unaltered, but the high susceptibility of TYK2 -/-mice resulted from an impaired tumor surveillance, and accordingly, TYK2 -/-A-MuLV-induced lymphomas were easily rejected after transplantation into WT hosts. The increased rate of leukemia/lymphoma formation was linked to a decreased in vitro cytotoxic capacity of TYK2 -/-NK and NKT cells toward tumor-derived cells. RAG2/TYK2 double-knockout mice succumbed to A-MuLV-induced leukemia/lymphoma faster than RAG2 -/-TYK2 +/-mice. This defines NK cells as key players in tumor surveillance in Abelson-induced malignancies. Our observations provide compelling evidence that TYK2 is an important regulator of lymphoid tumor surveillance. IntroductionThe JAK-STAT pathway regulates cell proliferation, differentiation, and survival in hematopoietic cells (1, 2). Binding of a cytokine to its cognate receptor activates receptor-associated JAKs which in turn mediate the subsequent tyrosine phosphorylation of STAT proteins. Phosphorylated STAT proteins form dimers, translocate to the nucleus, and bind to specific DNA elements to induce or modulate expression of target genes. Gene knockout studies in mice underlined the vital role of the JAK-STAT pathway for hematopoiesis and other developmental processes (3).Recent interest had focused on the role of the JAK-STAT pathway in tumor formation. Aberrant activation of JAK-STAT signaling had been shown in multiple solid tumors and leukemia (4-9). In particular, STAT3 and STAT5 have drawn much attention; both transcription factors display oncogenic properties when expressed ectopically. A constitutively active mutant of STAT3 was shown to transform rat fibroblasts (10), and the enforced expression of WT STAT5 in the lymphoid lineage induced T cell leukemia in mice (11). In addition, JAK1 has been implicated in transformation by the v-abl as well as by the v-src oncogene (12, 13), and constitutive activation of JAK2 as in the TEL-JAK2 oncogene suffices to induce leukemia in mice and humans (14, 15). On the other hand, JAK1 was shown to be a tumor suppressor downstream of IFN-γ in a B lymphoid tumor model (16). A role as tumor suppressor downstream of IFN-γ has also been attributed to STAT1 (17-21). STAT1 -/-mice have been repeatedly used to study the role of IFN-γ in tumorigenesis and tumor surveillance (18,19). Recent evidence also proposed that STAT1 acted as a tumor suppressor by modulating apoptosis (22).TYK2 has been initially defined as a mediator of IFN-α/β sign...

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Section: Discussionmentioning

confidence: 62%

TYK2 is a key regulator of the surveillance of B lymphoid tumors

Stoiber¹,

Kovacic²,

Schuster³

et al. 2004

J. Clin. Invest.

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“…Using a rat NK cell line transfected with LY49D or LY49A, Inngjerdingen et al have shown that ligation of LY49D increased migration toward CXCL10, whereas ligation of LY49A decreased migration. 12 Thus, CXCL10-transduced leukemia cell vaccines preferentially attract to the vaccine site NK cells that respond to this chemokine.…”

Section: Discussionmentioning

confidence: 99%

“…These chemokines attract activated T cells and natural killer (NK) cells. [11][12][13][14] CXCL10-deficient mice also had a defect in effector T-cell generation, indicating that CXCL10 might also be essential to T-cell adaptive immunity. 15 We therefore used the DA1-3b mouse model of AML to investigate if CXCL10 could induce an efficient antileukemic immune response.…”

Section: Introductionmentioning

confidence: 99%

NK cells that are activated by CXCL10 can kill dormant tumor cells that resist CTL-mediated lysis and can express B7-H1 that stimulates T cells

Saudemont

Jouy

Hétuin

et al. 2005

Blood

112

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“…6D). CXCL9 and CXCL10 chemokines were selected because they have been shown to be involved in the CTL-induced tumor regression in mice (26)(27)(28). Tumor samples of IL-13Ra2 DNA vaccine-treated mice collected on days 13 and 16 were positive for CXCL9 whereas control tumor samples were negative for this chemokine.…”

Section: Infiltration Of Cd4mentioning

confidence: 99%

Characterization of a Novel Human Tumor Antigen Interleukin-13 Receptor α2 Chain

Kawakami

Terabe²,

Kawakami³

et al. 2006

Cancer Research

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The interleukin (IL)-13 receptor A2 (IL-13RA2) chain is a primary binding and internalization subunit for a Th2-derived immune regulatory cytokine, IL-13. Although extremely high levels of IL-13RA2 chain are expressed on a variety of human tumor cells and specimens, its precise role in tumor immunology has not been defined. To investigate the role of IL-13RA2 in tumor immunity, we used D5 melanoma cells stably transfected with the human IL-13RA2 gene (D5A2) to assess the effect of an IL-13RA2 DNA vaccine in immunocompetent animals. Prophylactic immunization of mice with the IL-13RA2 DNA vaccine resulted in protection against D5A2 tumor development. In vivo depletion experiments in C57BL/6 and RAG-2 knockout mice indicated that both T and B cells, but not natural killer cells, were required for the tumor protection. In addition, antibody induced by the IL-13RA2 DNA vaccine showed a modest but significant inhibitory effect on D5A2 cells in vitro, suggesting that the antibody is biologically functional. The IL-13RA2 DNA vaccine also exhibited antitumor activity against established D5A2 tumors in mice. Histologic analysis of regressing tumors identified infiltration of CD4 + and CD8 + T cells and the expression of CXCL9 chemokine in tumors. Taken together, our results identify the human IL-13RA2 chain as a novel tumor rejection antigen. (Cancer Res 2006; 66(8): 4434-42)

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Activating and Inhibitory Ly49 Receptors Modulate NK Cell Chemotaxis to CXC Chemokine Ligand (CXCL) 10 and CXCL12

Cited by 30 publications

References 45 publications

TYK2 is a key regulator of the surveillance of B lymphoid tumors

TYK2 is a key regulator of the surveillance of B lymphoid tumors

NK cells that are activated by CXCL10 can kill dormant tumor cells that resist CTL-mediated lysis and can express B7-H1 that stimulates T cells

Characterization of a Novel Human Tumor Antigen Interleukin-13 Receptor α2 Chain

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