In Vivo Survival and Homeostatic Proliferation of Natural Killer Cells

Prlic, Martin; Blazar, Bruce R.; Farrar, Michael A.; Jameson, Stephen C.

doi:10.1084/jem.20021847

Cited by 213 publications

(207 citation statements)

References 62 publications

Supporting

Mentioning

192

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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...

show abstract

Section: Tam Control Of Natural-killer-cell Differentiationmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

View full text Add to dashboard Cite

show abstract

“…Although the importance of IL-15 in this process is undisputed [19,20,[22][23][24], it is unclear whether IL-15 1) acts on early NK cell precursors, 2) is only needed at the terminal steps of NK cell development or 3) is important role in maintaining lymphocyte proliferation and homeostasis. To investigate this process, we cultured human umbilical cord blood (UCB) CD34 + Lin − CD38 − primitive progenitors on AFT024.…”

Section: Resultsmentioning

confidence: 99%

“…In human studies, IL-15 is made by stroma and macrophages [21,22]. The importance of IL-15 in the homeostasis of NK [23,24] and T-cells provides further evidence of the physiologic role for this cytokine in the immune system [20]. These studies do not distinguish between the role of IL-15 in homeostatic expansion and survival versus differentiation.…”

Section: Introductionmentioning

confidence: 99%

Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15

McCullar

Oostendorp

Panoskaltsis‐Mortari

et al. 2008

Experimental Hematology

View full text Add to dashboard Cite

Objective-Human NK cell maturation involves the orderly acquisition of NK cell receptors. Our aim was to understand how stromal interactions and cytokines are important in this developmental process.Methods-Human UCB CD34 + /Lin − /CD38 − cells were cultured on two murine stromal cell lines (AFT024 and EL08-1D2) in a switch culture to study NK cell development.Results-When human progenitors were cultured on AFT024 with IL-3 and Flt3-L in the absence of IL-15, NK cell differentiation occurred, albeit at low frequency. These conditions favored the accumulation of CD56 − NK cell precursors (CD34 + CD7 − , CD34 + CD7 + and CD34 − CD7 + cells), which are populations rare in adult blood but abundant in fresh UCB. In secondary culture, addition of IL-3 or IL-3+Flt3L to IL-15 increased the absolute number of CD56 + NK cells from precursors and the acquisition of CD94 and KIR. To further explore the microenvironment in early NK cell maturation, a cell line derived from murine embryonic liver (EL08-1D2) was studied. NK cell development and KIR acquisition was superior with EL08-1D2 which supported the differentiation of NK cell precursors, NK cell commitment, and proliferation.Conclusion-Although the earliest events in NK cell maturation do not require exogenous human IL-15, it is required at a later stage of NK cell commitment. At a minimum, murine stroma, IL-3, and Flt3-L are required to recapitulate early NK cell development and differentiation into distinct NK cell precursors. EL08-1D2 induces KIR acquisition suggesting that extrinsic signals in NK cell development are conserved between mouse and man.

show abstract

“…NK cells do not undergo homeostatic proliferation when transferred into NK cell-replete hosts (Prlic et al 2003). In NK cell-deficient hosts, however, adoptively transferred NK cells do proliferate (Prlic et al 2003;Jamieson et al 2004), and the kinetics of their expansion and contraction mirror those of the Ly49H + NK cell subset during MCMV infection (Sun et al 2011).…”

Section: Generating Nk Cell Memory Through Homeostatic Proliferationmentioning

confidence: 99%

Sweet Is the Memory of Past Troubles: NK Cells Remember

Hendricks

Min‐Oo

Lanier

2015

Natural Killer Cells

View full text Add to dashboard Cite

Natural killer (NK) cells are important in host defense against tumors and microbial pathogens. Recent studies indicate that NK cells share many features with the adaptive immune system, and like B cells and T cells, NK cells can acquire immunological memory. Here, we review evidence for NK cell memory and the molecules involved in the generation and maintenance of these self-renewing NK cells that provide enhanced protection of the host.

show abstract

In Vivo Survival and Homeostatic Proliferation of Natural Killer Cells

Cited by 213 publications

References 62 publications

Immunobiology of the TAM receptors

Immunobiology of the TAM receptors

Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15

Sweet Is the Memory of Past Troubles: NK Cells Remember

Contact Info

Product

Resources

About