Leukemic challenge unmasks a requirement for PI3Kδ in NK cell–mediated tumor surveillance

Zebedin, Eva; Simma, Olivia; Schuster, Christian; Putz, Eva Maria; Fajmann, Sabine; Warsch, Wolfgang; Eckelhart, Eva; Stoiber, Dagmar; Weisz, Eva; Schmid, Johannes A.; Pickl, Winfried F.; Baumgartner, Christian; Valent, Peter; Piekorz, Roland P.; Freissmuth, Michael; Sexl, Veronika

doi:10.1182/blood-2008-02-139105

Cited by 45 publications

(47 citation statements)

References 48 publications

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“…The well-known NK-target cell line YAC-1, which lacks MHCI expression, was used as a positive control in all experimental settings. 39 To investigate the effect of T cells, we performed in vitro T-cell cytotoxicity assays. Although no specific killing over the baseline was observed against E-myc/p53 ϩ/Ϫ tumor targets, E-myc/vav-bcl-2 tumor targets were efficiently recognized and lysed by cytotoxic T lymphocytes ( Figure 5E).…”

Section: Nk and T Cell-mediated Cytotoxicity Is Enhanced On Bcl-2 Expmentioning

confidence: 99%

The cooperating mutation or “second hit” determines the immunologic visibility toward MYC-induced murine lymphomas

Schuster

Berger

Hoelzl

et al. 2011

Blood

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In E-myc transgenic animals lymphoma formation requires additional genetic alterations, which frequently comprise loss of p53 or overexpression of BCL-2. We describe that the nature of the "second hit" affects the ability of the immune system to contain lymphoma development. Tumors with disrupted p53 signaling killed the host more rapidly than BCL-2 overexpressing ones. Relaxing immunologic control, using Tyk2 ؊/؊ mice or by Ab-mediated depletion of CD8 ؉ T or natural killer (

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Section: Nk and T Cell-mediated Cytotoxicity Is Enhanced On Bcl-2 Expmentioning

confidence: 99%

The cooperating mutation or “second hit” determines the immunologic visibility toward MYC-induced murine lymphomas

Schuster

Berger

Hoelzl

et al. 2011

Blood

Self Cite

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“…2 The genes encoding the PI3K catalytic and regulatory chains are members of multi-gene families. Historically, the p110a isoform has been the best-characterized catalytic subunit; however, it has been recently shown that the p110d isoform may play a larger role in leukemogenesis [3][4][5] and tumor surveillance than expected previously. The activation of the PI3Kd isoform does not appear to be due to genetic mutations.…”

Section: Introductionmentioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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“…In contrast to this notion, Zebedin et al (45) have recently shown evidence of impaired NK cell cytotoxicity in p110␦ Ϫ/Ϫ mice on a mixed (129xC57BL/6) background. We think the discrepancy with the results published by us and others, using mice on C57BL/6 (29,36) or C57BL/10 background (28), could be due to the genetic background itself.…”

Section: Discussionmentioning

confidence: 73%

p110γ and p110δ isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease

Saudemont

Garçon

Yadi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The mechanisms that regulate NK cell trafficking are unclear. Phosphoinositide-3 kinases (PI3K) control cell motility and the p110␥ and p110␦ isoforms are mostly expressed in leukocytes, where they transduce signals downstream of G protein coupled receptors (GPCR) or tyrosine kinase receptors, respectively. Here, we set out to determine the relative contribution of p110␥ and p110␦ to NK cell migration in mice. Using a combination of single-cell imaging analysis of transgenic cells reporting on PI3K activity in real time and small molecule inhibitors of p110␥ and p110␦, we show here that the tyrosine-kinase coupled p110␦ is linked to GPCR signaling and, depending on the GPCR, may even be preferentially activated over p110␥. Using gene-targeted mice, we showed that both isoforms were essential for NK cell chemotaxis to CXCL12 and to CCL3 and, in vivo, for normal NK cell migration during pregnancy and to the inflamed peritoneum. By contrast, only p110␦ was indispensable for chemotaxis to S1P and CXCL10 and for NK cell distribution throughout lymphoid and nonlymphoid tissues and for extravasation to tumors. These results implicate p110␦ downstream of GPCRs in NK cells and highlight its nonredundant role as a key regulator of NK cell trafficking in health and disease.cell signaling ͉ cell trafficking ͉ innate immunity N K cells develop primarily in the bone marrow, thymus and lymph nodes and are distributed in lymphoid tissues, and in many organs throughout the body, including uterus, liver, lungs, intestine and peritoneum. Resident and recruited NK cells play important roles in reproduction and in immunological surveillance (1-3), and therefore migration is an important aspect of NK cell biology. Lymphocyte migration is organized by selectins, chemokines and integrins (4) and although some of the factors regulating NK cell trafficking are emerging, the picture is incomplete (1, 5). For example, L-selectin is indispensible for NK cell migration to lymph nodes (6), and some chemokines and chemokine receptors have been identified that orchestrate NK cell egression from the bone marrow (7), migration to the decidua (2), sites of inflammation (3), activated lymph nodes (8), and tumors (9-10). Recently, the GPCR sphingosine 1-phosphate receptor 5 (S1P 5 ) has been identified as a key regulator of NK cell distribution (11). These studies indicate that the mechanisms that regulate NK cell trafficking are distinct from those that regulate the trafficking of other lymphocytes and therefore, in view of the promise of pharmacological inhibitors of leukocyte trafficking to treat disease (12), it is important to know how target molecules regulate trafficking of all leukocyte subsets.Phosphoinositide 3-kinases (PI3Ks) generate lipid second messengers that control disparate aspects of cell biology, including growth, survival, metabolism and motility (13) and are prominent pharmacological targets (14, 15). Class I PI3Ks are the most thoroughly studied in mammalian cells and are composed of 2 subclasses, which include 4 catalytic iso...

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Leukemic challenge unmasks a requirement for PI3Kδ in NK cell–mediated tumor surveillance

Cited by 45 publications

References 48 publications

The cooperating mutation or “second hit” determines the immunologic visibility toward MYC-induced murine lymphomas

The cooperating mutation or “second hit” determines the immunologic visibility toward MYC-induced murine lymphomas

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

p110γ and p110δ isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease

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