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Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor.

ABSTRACT: Cytotoxic lymphocyte maturation factor (CLMF) is a disulfide-bonded heterodimeric lymphokine that (i) acts as a growth factor for activated T cells independent of interleukin 2 and (ii) synergizes with suboptimal concentrations of interleukin 2 to induce lymphokine-activated killer cells. We now report the cloning and expression of both human CLMF subunit cDNAs from a lymphoblastoid B-cell line, NC-37. The two subunits represent two distinct and unrelated gene products whose mRNAs are coordinately induced upon activation of NC-37 cells. Coexpression of the two subunit cDNAs in COS cells is necessary for the secretion of biologically active CLMF; COS cells transfected with either subunit cDNA alone do not secrete bioactive CLMF. Recombinant CLMF expressed in mammalian cells displays biologic activities essentially identical to natural CLMF, and its activities can be neutralized by monoclonal antibodies prepared against natural CLMF. Since this heterodimeric protein displays the properties of an interleukin, we propose that CLMF be given the designation interleukin 12.

SUBMITTER: Gubler U

PROVIDER: S-EPMC51614 | biostudies-other | 1991 May

REPOSITORIES: biostudies-other

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Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor.

Gubler U U Chua A O AO Schoenhaut D S DS Dwyer C M CM McComas W W Motyka R R Nabavi N N Wolitzky A G AG Quinn P M PM Familletti P C PC

Proceedings of the National Academy of Sciences of the United States of America 19910501 10

Cytotoxic lymphocyte maturation factor (CLMF) is a disulfide-bonded heterodimeric lymphokine that (i) acts as a growth factor for activated T cells independent of interleukin 2 and (ii) synergizes with suboptimal concentrations of interleukin 2 to induce lymphokine-activated killer cells. We now report the cloning and expression of both human CLMF subunit cDNAs from a lymphoblastoid B-cell line, NC-37. The two subunits represent two distinct and unrelated gene products whose mRNAs are coordinate ...[more]

PMID: 1674604

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Project description:Immunotherapy, which is seen as a major tool for cancer treatment, requires, in some cases, the presence of several agents to maximize its effects. Adjuvants can enhance the effect of other agents. However, despite their long-time use, only a few adjuvants are licensed today, and their use in cancer treatment is rare. Azoximer bromide, marketed under the trade name Polyoxidonium® (PO), is a copolymer of N-oxidized 1,4-ethylenepiperazine and (N-carboxyethyl)-1,4-ethylene piperazinium bromide. It has been described as an immune adjuvant and immunomodulator that is clinically used with excellent tolerance. PO is used in the treatment and prophylaxis of diseases connected with damage to the immune system, and there is interest in testing it in antitumor therapy. We show here that PO treatment for 1 week induced positive pathological changes in 6 out of 20 patients with breast cancer, including complete response in a triple-negative patient. This correlated with an increased tumor CD4+ T-lymphocyte infiltration. The immune effects of PO are associated with myeloid cell activation, and little is known about the action of PO on lymphocyte lineages, such as natural killer (NK) and T cells. We reveal that PO increases T-cell proliferation in vitro without negative effects on any activation marker. PO does not affect dendritic cell (DC) viability and increases the expansion of immature DC (iDC) and mature DC (mDC) at 100 μg/ml, and it stimulates expression of several DC co-stimulatory molecules, inducing the proliferation of allogeneic T cells. In contrast, PO decreases DC viability when added at day 5 post-expansion. PO is not toxic for NK cells at doses up to 100 μM and does not affect their activation, maturation, and cytotoxicity but tends to increase degranulation. This could be beneficial against target cells that show low sensitivity to NK cells, e.g., solid tumor cells. Finally, we have found great variability in PO response between donors. In summary, our in vitro results show that PO increases the number of costimulatory molecules on DC that prime T cells, favoring the production of effector T cells. This may support the future clinical development of PO in cancer treatment.

Project description:PurposeTo identify CD8+ T lymphocyte-related coexpressed genes that increase CD8+ T lymphocyte proportions in breast cancer and to elucidate the underlying mechanisms among relevant genes in the tumor microenvironment.MethodWe obtained breast cancer expression matrix data and patient phenotype following information from TCGA-BRCA FPKM. Tumor purity, immune score, stromal score, and estimate score were calculated using the estimate package in R. The CD8+ T lymphocyte proportions in each breast carcinoma sample were estimated using the CIBERSORT algorithm. The samples with p < 0.05 were considered to be significant and were taken into the weighted gene coexpression network analysis. Based on the CD8+ T lymphocyte proportion and tumor purity, we generated CD8+ T lymphocyte coexpression networks and selected the most CD8+ T lymphocyte-related module as our interested coexpression modules. We constructed a CD8+ T cell model based on the least absolute shrinkage and selection operator method (LASSO) regression model and robust model and evaluate the prediction ability in different subgroups.ResultsA breast carcinoma CD8+ T lymphocyte proportion coexpression yellow module was determined. The coexpression genes in the yellow module were determined to increase the CD8+ T lymphocyte proportion levels in breast cancer patients. The yellow module was significantly enriched in the antigen presentation process, cellular response to interferon-gamma, and leukocyte proliferation. Subsequently, we generated CD8+ T cell-related genes lasso regression risk model and robust model, and eight genes were taken into the risk model. The risk score showed significant prognostic ability in various subgroups. Expression levels of proteins, encoded by CD74, were lower in the breast carcinoma samples than in normal tissue, suggesting expression differences at both the mRNA and the protein levels.ConclusionThese eight CD8+ T lymphocyte proportion coexpression genes increase CD8+ T lymphocyte in breast cancer by an antigen presentation process. The mechanism might suggest new pathways to improve outcomes in patients who do not benefit from immune therapy.

Dataset Information

Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor.

Publications

Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor.

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