Rapid activation receptor– or IL-2–induced lytic granule convergence in human natural killer cells requires Src, but not downstream signaling

James, Ashley M.; Hsu, Hsiang Ting; Dongre, Prachi; Uzel, Gülbû; Mace, Emily M.; Banerjee, Pinaki P.; Orange, Jordan S.

doi:10.1182/blood-2012-06-437012

Cited by 60 publications

(77 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Prior studies have shown that the polarization of perforin-containing granules toward the site of tumor contact is dependent on the activation of PI3K¡ERK1/2 (61), which is dependent on Src family kinases (62). These data were consistent with our observation that the polarization of perforin-containing granules toward the site of contact with C. neoformans is dependent on PI3K¡ERK1/2 (15) and Src family kinases (present data).…”

Section: Discussionsupporting

confidence: 83%

Requirement and Redundancy of the Src Family Kinases Fyn and Lyn in Perforin-Dependent Killing of Cryptococcus neoformans by NK Cells

et al. 2013

View full text Add to dashboard Cite

Natural killer (NK) cells directly recognize and kill fungi, such as the pathogenic fungus Cryptococcus neoformans, via cytolytic mechanisms. However, the precise signaling pathways governing this NK cell microbicidal activity and the implications for fungal recognition are still unknown. Previously, it was reported that NK cell anticryptococcal activity is mediated through a conserved phosphatidylinositol 3-kinase-extracellular signal-regulated kinase 1/2 (PI3K-ERK1/2) pathway. Using YT (a human NK-like cell line) and primary human NK cells, we sought to identify the upstream, receptor-proximal signaling elements that led to fungal cytolysis. We demonstrate that Src family kinases were activated in response to C. neoformans. Furthermore, pharmacologic inhibition with an Src kinase inhibitor blocked C. neoformans-induced downstream activation of PI3K and ERK1/2 and abrogated cryptococcal killing. At the same time, the inhibitor disrupted the polarization of perforin-containing granules toward the NK cell-cryptococcal synapse but had no effect on conjugate formation between the organism and the NK cell. Finally, small interfering RNA (siRNA) double (but not single) knockdown of two Src family kinases, Fyn and Lyn, blocked cryptococcal killing. Together these data demonstrate a mechanism whereby the Src family kinases, Fyn and Lyn, redundantly mediate anticryptococcal activity through the activation of PI3K and ERK1/2, which in turn facilitates killing by inducing the polarization of perforin-containing granules to the NK cell-cryptococcal synapse.

show abstract

Section: Discussionsupporting

confidence: 83%

Requirement and Redundancy of the Src Family Kinases Fyn and Lyn in Perforin-Dependent Killing of Cryptococcus neoformans by NK Cells

et al. 2013

View full text Add to dashboard Cite

show abstract

“…This finding is supported by previous reports, demonstrating that both Stx3 and Stx11 are capable of forming a SNARE complex with SNAP23 and VAMP8 (52)(53)(54). Many other changes take place with IL-2 activation of cells, including clustering of granules (55). However, our studies reveal changes that could compensate for lost SNARE interactions, which are critical for NK and CTL function.…”

Section: Discussionsupporting

confidence: 73%

Syntaxin binding mechanism and disease-causing mutations in Munc18-2

Hackmann

Graham

Ehl³

et al. 2013

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

View full text Add to dashboard Cite

Significance Understanding the molecular mechanisms that control secretion from cytotoxic T lymphocytes (CTL) and natural killer (NK) cells is the key for understanding how these cells destroy virally infected and tumourigenic cells. Precisely how mutations in Munc18-2 and syntaxin 11 (Stx11) give rise to loss of CTL and NK function and severe immunodeficiency is poorly understood. In this study we present a crystal structure of human Munc18-2 and analyze the disease-causing mutations. Our findings reveal a mechanism that allows Munc18-2 to selectively bind Stx11 and identify potential surrogate binding partners, which could restore Munc18-Stx function upon IL-2 activation.

show abstract

“…5C). As granule convergence to the MTOC is an early step in the preparation of an NK cell for cytotoxicity 32,33 this is an unexpected finding; however, movement and exocytosis of secretory lysosomes in NK cells can occur independently from MTOC polarization. 32,[34][35][36] As direct visualization of conjugate formation clearly documents an extension and flattening of TIML-NK cell shape toward the immunological synapse (IS) (Fig.…”

Section: Timl-nk Cells Display Enhanced Perforin Synthesismentioning

confidence: 99%

Tumor-priming converts NK cells to memory-like NK cells

et al. 2017

Self Cite

View full text Add to dashboard Cite

Fascinating earlier evidence suggests an intrinsic capacity of human natural killer (NK) cells to acquire adaptive immune features in the context of cytomegalovirus (CMV) infection or pro-inflammatory cytokine stimulation. Since the role of memory NK cells in cancer has so far remained elusive and adoptive NK cell transfer in relapsing pediatric acute B cell precursor leukemia (BCP-ALL) patients awaits improvement, we asked the question whether tumor-priming could promote the generation of memory NK cells with enhanced graft-vs.-leukemia (GvL) reactivity. Here, we provide substantial evidence that priming of naive human NK cells with pediatric acute B cell leukemia or acute myeloid leukemia specimens induces a functional conversion to tumor-induced memory-like (TIML)-NK cells displaying a heightened tumorspecific cytotoxicity and enhanced perforin synthesis. Cell cycles analyses reveal that tumor-priming sustainably alters the balance between NK cell activation and apoptosis in favor of survival. In addition, gene expression patterns differ between TIML-and cytokine-induced memory-like (CIML)-NK cells with the magnitude of regulated genes being distinctly higher in TIML-NK cells. As such, the tumor-induced conversion of NK cells triggers the emergence of a so far unacknowledged NK cell differentiation stage that might promote GvL effects in the context of adoptive cell transfer.

show abstract

Rapid activation receptor– or IL-2–induced lytic granule convergence in human natural killer cells requires Src, but not downstream signaling

Abstract: Key Points Src signals are required for specific receptor and cytokine activation–induced rapid reorientation of lytic granules to the MTOC in NK cells.

Cited by 60 publications

References 49 publications

Requirement and Redundancy of the Src Family Kinases Fyn and Lyn in Perforin-Dependent Killing of Cryptococcus neoformans by NK Cells

Requirement and Redundancy of the Src Family Kinases Fyn and Lyn in Perforin-Dependent Killing of Cryptococcus neoformans by NK Cells

Syntaxin binding mechanism and disease-causing mutations in Munc18-2

Tumor-priming converts NK cells to memory-like NK cells

Contact Info

Product

Resources

About