The Mouse Tumor Cell Lines EL4 and RMA Display Mosaic Expression of NK-Related and Certain Other Surface Molecules and Appear to Have a Common Origin

Gays, Frances; Unnikrishnan, Meera; Shrestha, Sunil; Fraser, Karen P.; Brown, Adam R.; Tristram, Colin M. G.; Chrzanowska-Lightowlers, Zofia M.A.; Brooks, Colin G.

doi:10.4049/jimmunol.164.10.5094

Cited by 31 publications

(30 citation statements)

References 84 publications

(46 reference statements)

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“…Thus, different cell types in the original line could have been subject to selection under different growth conditions. EL4 was characterized as an "NK T-cell tumor" by Gays and colleagues (11), NK referring to natural killer cells. They noted that NK-related markers are expressed in a fluctuating manner, even in clonal EL4 cell lines, ascribing this to an epigenetic process.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of Ccn4 and Other Genes Between Metastatic and Non-metastatic EL4 Mouse Lymphoma Cells

Chahal

Legaspi

et al. 2016

CGP

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EL4 is a murine lymphoma cell line developed in 1945 by treating C57 black mice with 9:10-dimethyl-1:2-benzanthracene (1). The cells were originally propagated in animal hosts, prior to adaptation to cell culture. EL4 cells were used for many years as a source of interleukin-2 (IL2), which they secrete when treated with phorbol 12-myristate 13-acetate (PMA).The EL4 cell line originally provided to us, by a colleague at the University of Washington, was heterogeneous with respect to PMA response. We, therefore, developed and characterized EL4 sub-lines. Wild-type (WT)-derived cell lines, which are PMA responsive, grow readily in suspension culture as did the original strain. Variant (V)-derived (PMA-resistant) sub-lines were selected for enhanced adhesion to tissue culture plastic (2). Clonal lines were developed from both cell types by limiting dilution (3). The PMA sensitivity of WT-derived cells, as reflected by PMA-induced IL2 production and mitogen-activated protein kinase (ERK1/2) activation, has been attributed to expression of Ras guanyl nucleotide releasing protein 1 (RasGRP1), which binds PMA and directly activates Ras (4); V-derived cells do not express RasGRP1.Clonal EL4 cell lines were used for experimental metastasis studies in syngeneic mice, with WT2 and V7 as prototypes (5, 6). WT2 cells do not form tumors (nonmetastatic), while V7 cells form liver tumors (metastatic) after tail vein injection. 'Metastasis' more strictly refers to tumorigenesis in this model, since circulating EL4 cells home to the liver to form tumors (5). The clonal C5 cell line was developed after stably overexpressing human hemagllutinin (HA)-tagged phospholipase D2 (PLD2) in V7 cells in order to characterize the signaling role of PLD2 using a cell line expressing little or no endogenous PLD2 (5). As compared to V7, C5 cells exhibit increased cell migration (7) and tumor growth (5), providing an early example of the positive role of PLD2 in tumorigenesis.This report presents data from microarray analyses comparing transcripts expressed by these three EL4 cell types, with the goal of further defining their phenotypes.

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Section: Discussionmentioning

confidence: 99%

Differential Expression of Ccn4 and Other Genes Between Metastatic and Non-metastatic EL4 Mouse Lymphoma Cells

Chahal

Legaspi

et al. 2016

CGP

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“…RMA (H-2 b ) is a sub-line of RBL-5, originating from the EL-4 T-cell lymphoma, induced in a B6 mouse [46,47]. RMA-S is a TAP-2-deficient variant of RMA, generated by mutagenesis followed by selection for MHC class I deficiency [4,48,49].…”

Section: Tumor Cell Linesmentioning

confidence: 99%

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

et al. 2010

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Missing-self-reactivity can be mimicked by blocking self-specific inhibitory receptors on NK cells, leading to increased rejection of syngeneic tumor cells. Using a mouse model, we investigated whether Ab-mediated blocking of inhibitory receptors, to a degree where NK cells rejected syngeneic tumor cells, would still allow self-tolerance toward normal syngeneic cells. Ly49C/I inhibitory receptors on C57BL/6 (H-2 b ) NK cells were blocked with F(ab') 2 fragments of the mAb 5E6. Inhibitory receptor blockade in vivo caused rejection of i.v. inoculated fluorescence-labeled syngeneic lymphoma line cells but not of syngeneic spleen cells, BM cells or lymphoblasts. The selective rejection of tumor cells was NK celldependent and specifically induced by Ly49C/I blockade. Moreover, selective tumor rejection was maintained after treatment with 5E6 F(ab') 2 for 9 wk, arguing against the induction of NK cell anergy or autoreactivity during this time. Combination therapy using 5E6 F(ab') 2 together with high dose IL-2 treatment further increased lymphoma cell rejection. In addition, combination therapy reduced growth of melanoma cell line tumors established by s.c. inoculation 3 days before start of treatment. Our results demonstrate that inhibitory receptor blockade does not result in attack on normal cells, despite potent reactivity against MHC class I-expressing tumors.

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“…For NK cell depletion, mice were administered 200 mg aNK1.1 (PK136, Mabtech). RMA (H-2 b ) originates from the EL-4 T-cell leukemia (28) and RMA-S is a TAP2-deficient variant of RMA (5,29). RMA and RMA-S cells were propagated as ascites lines in sublethally irradiated (4-Gy dose) B6 mice.…”

Section: Mice and Tumorsmentioning

confidence: 99%

Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response

Wagner

Wickström

Tallerico

et al. 2016

Cancer Immunology Research

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Natural killer (NK) cells are most efficient if their targets do not express self MHC class I, because NK cells carry inhibitory receptors that interfere with activating their cytotoxic pathway. Clinicians have taken advantage of this by adoptively transferring haploidentical NK cells into patients to mediate an effective graftversus-leukemia response. With a similar rationale, antibody blockade of MHC class I-specific inhibitory NK cell receptors is currently being tested in clinical trials. Both approaches are challenged by the emerging concept that NK cells may constantly adapt or "tune" their responsiveness according to the amount of self MHC class I that they sense on surrounding cells. Hence, these therapeutic attempts would initially result in increased killing of tumor cells, but a parallel adaptation process might ultimately lead to impaired antitumor efficacy. We have investigated this question in two mouse models: inhibitory receptor blockade in vivo and adoptive transfer to MHC class I-disparate hosts. We show that changed self-perception via inhibitory receptors in mature NK cells reprograms the reactivity such that tolerance to healthy cells is always preserved. However, reactivity against cancer cells lacking critical MHC class I molecules (missing self-reactivity) still remains or may even be increased. This dissociation between activity against healthy cells and tumor cells may provide an answer as to why NK cells mediate graftversus-leukemia effects without causing graft-versus-host disease and may also be utilized to improve immunotherapy.

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The Mouse Tumor Cell Lines EL4 and RMA Display Mosaic Expression of NK-Related and Certain Other Surface Molecules and Appear to Have a Common Origin

Cited by 31 publications

References 84 publications

Differential Expression of Ccn4 and Other Genes Between Metastatic and Non-metastatic EL4 Mouse Lymphoma Cells

Differential Expression of Ccn4 and Other Genes Between Metastatic and Non-metastatic EL4 Mouse Lymphoma Cells

In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2

Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response

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