Lymphotoxin α1β2: a critical mediator in Vα14i NKT cell differentiation

Franki, Ann Sophie; Beneden, Katrien Van; Dewint, Pieter; I, Meeus; Veys, Eric; Deforce, Dieter; Elewaut, Dirk

doi:10.1016/j.molimm.2004.07.020

Cited by 10 publications

(5 citation statements)

References 40 publications

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“…Although thymic stromal cells do not directly present ligands for iNKT-cell selection, these cells do play critical accessory roles in the development of iNKT cells. In particular, NF-κB2 signaling in thymic stromal cells is required for iNKT-cell development, and the IAP antagonists can modulate this pathway, suggesting that the IAP antagonists may act on these cells (40, 52).…”

Section: Discussionmentioning

confidence: 99%

IAP Antagonists Enhance Cytokine Production from Mouse and Human iNKT Cells

Clancy‐Thompson

Ali

Bruck

et al. 2018

Cancer Immunology Research

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Inhibitor of apoptosis protein (IAP) antagonists are in clinical trials for a variety of cancers, and mouse models show synergism between IAP antagonists and anti-PD-1 immunotherapy. Although IAP antagonists affect the intrinsic signaling of tumor cells, their most pronounced effects are on immune cells and the generation of antitumor immunity. Here, we examined the effects of IAP antagonism on T-cell development using mouse fetal thymic organ culture and observed a selective loss of iNKT cells, an effector cell type of potential importance for cancer immunotherapy. Thymic iNKT-cell development probably failed due to increased strength of TCR signal leading to negative selection, given that mature iNKT cells treated with IAP antagonists were not depleted, but had enhanced cytokine production in both mouse and human cultures. Consistent with this, mature mouse primary iNKT cells and iNKT hybridomas increased production of effector cytokines in the presence of IAP antagonists. administration of IAP antagonists and α-GalCer resulted in increased IFNγ and IL-2 production from iNKT cells and decreased tumor burden in a mouse model of melanoma lung metastasis. Human iNKT cells also proliferated and increased IFNγ production dramatically in the presence of IAP antagonists, demonstrating the utility of these compounds in adoptive therapy of iNKT cells. .

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Section: Discussionmentioning

confidence: 99%

IAP Antagonists Enhance Cytokine Production from Mouse and Human iNKT Cells

Clancy‐Thompson

Ali

Bruck

et al. 2018

Cancer Immunology Research

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“…This finding is constant with another study that has shown that lymphotoxin B is expressed by activated NK cells (23). Lymphotoxin B is important for the development of secondary lymph nodes and it stimulates the growth of NK and NKT cells (24;25). The up-regulation of LTB may be important for the expansion of cultured NK cells.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Analysis of Ex Vivo Expanded and Freshly Isolated NK Cells From Cancer Patients

Park

Jin²,

Sabatino³

et al. 2010

Journal of Immunotherapy

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Summary The infusion of natural killer (NK) cells is a promising therapy for patients with advanced malignancies. Clinical expanded NK cell products were compared to freshly isolated NK cells. Autologous peripheral blood mononuclear cells were collected by apheresis from 8 patients. NK cells were isolated by anti-CD3 negative selection followed by anti-CD56 positive selection. They were then expanded by coculture with IL-2 and an irradiated EBV-transformed lymphoblastoid cell line (EBV-TM-LCL) to produce 14 NK products. Molecular changes in the 14 NK cell products were characterized using gene and microRNA expression microarrays. EBV-TM-LCL feeder cells from 3 lots were also analyzed since they were expanded for over 90 days and each lot was used for multiple NK cell expansions. The gene expression profiles among the 3 EBV-TM-LCL lots used showed no differences and were not affected by their time in culture. Freshly isolated and expanded NK cells had distinct gene and microRNA expression profiles. Compared to fresh NK cells, expanded NK cells overexpressed 1,098 genes and 28 human microRNAs. Genes in the crosstalk between dendritic cells and NK cells and metabolic pathways were up-regulated in expanded NK cells, while genes in a number of immune function pathways were down-regulated. Among all the most up-regulated genes were the NK cell activating receptor natural cytotoxicity triggering receptor 3 (NCR3), myxovirus restistance 1 (MX1), lymphotoxin β (LTB) and BCL2-associated X protein (BAX) Although some expanded NK cell product variability was observed, perhaps related to patient factors, further studies on larger numbers of products will be needed to determine the impact of these differences on clinical outcomes.

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“…The alternative pathway and RelB may also have a specific role in nonhematopoietic cells required for thymic iNKT formation (Elewaut et al 2003;Sivakumar et al 2003;Franki et al 2005), although recent reports suggest that LTbRmediated activation of this pathway may be primarily required for thymic export/peripheral colonization of these cells and not their development (Franki et al 2006;Vallabhapurapu et al 2008). …”

Section: Nf-kb and Lymphocytesmentioning

confidence: 99%