Interleukin (IL)-15Rα–deficient Natural Killer Cells Survive in Normal but Not IL-15Rα–deficient Mice

Koka, Rima; Burkett, Patrick R.; Chien, Marcia; Chai, Sophia; Chan, Faye; Lodolce, James P.; Boone, David L.; Ma, Averil

doi:10.1084/jem.20021836

Cited by 237 publications

(223 citation statements)

References 45 publications

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“…Analyses of both IL-15-deficient and IL-15 receptor (IL-15R)-deficient mice have demonstrated that this cytokine promotes the differentiation of NK-cell precursors (CD122 + NK1.1 − cells) into immature NK cells (CD122 + NK1.1 + cells), and have additionally suggested that IL-15 also operates at the slightly later stages of NK-cell maturation during which TAM signalling is required [77][78][79][80][81] . It is therefore interesting that a physical and physiological association between the TAM receptor AXL and the α-subunit of the IL-15R has been demonstrated 82 .…”

Section: Tam Control Of Natural-killer-cell Differentiationmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

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Section: Tam Control Of Natural-killer-cell Differentiationmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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“…12 IL-15 and IL-15Ra are necessary for the differentiation of NK cells from lymphoid precursors and for their steady-state survival. 13,15,16 IL-15 is mitogenic for NK cells, enhances secretion of pro-inflammatory cytokines and upregulates their cytolytic machinery. 12,17 The multimeric receptor for IL-15 encompasses two signaling subunits IL-2Rb (CD122) and IL-2Rg (CD132), while the high-affinity specific chain (IL-15Ra) makes limited or no contribution to signaling.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells

et al. 2008

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“…Because IL-15R␣ Ϫ/Ϫ mice lack NK cells (26), we used IL-15R␣-deficient chimeric mice in which bone marrow from IL-15R␣-deficient mice was used to reconstitute irradiated wt recipients. In these chimeric mice, host cells expressing IL-15R␣ efficiently present IL-15 in trans to IL-15R␣-null NK cells promoting their development and survival (29,35).…”

Section: Impact Of Il-15r␣ On Nk Cells In Modulating Selective Prolifmentioning

confidence: 99%

“…IL-15R␣-deficient chimeric mice were generated, as previously described (35). Briefly, bone marrow was harvested from IL-15R␣ Ϫ/Ϫ mice that had been backcrossed to B6 mice for at least eight generations or from wildtype (wt) B6 mice.…”

Section: Il-15r␣-deficient Chimeric Micementioning

confidence: 99%

DAP12 Signaling Directly Augments Proproliferative Cytokine Stimulation of NK Cells during Viral Infections

French

Sjölin

Kim

et al. 2006

The Journal of Immunology

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NK cells vigorously proliferate during viral infections. During the course of murine CMV infection, this response becomes dominated by the preferential proliferation of NK cells that express the activation receptor Ly49H. The factors driving such selective NK cell proliferation have not been characterized. In this study, we demonstrate that preferential NK cell proliferation is dependent on DAP12-mediated signaling following the binding of Ly49H to its virally encoded ligand, m157. Ly49H signaling through DAP12 appears to directly augment NK cell sensitivity to low concentrations of proproliferative cytokines such as IL-15. The impact of Ly49H-mediated signaling on NK cell proliferation is masked in the presence of high concentrations of proproliferative cytokines that nonselectively drive all NK cells to proliferate.

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Interleukin (IL)-15Rα–deficient Natural Killer Cells Survive in Normal but Not IL-15Rα–deficient Mice

Cited by 237 publications

References 45 publications

Immunobiology of the TAM receptors

Immunobiology of the TAM receptors

Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells

DAP12 Signaling Directly Augments Proproliferative Cytokine Stimulation of NK Cells during Viral Infections

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