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Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells.

ABSTRACT: Inflammation likely has a role in the early genesis of certain malignancies. Interleukin (IL)-15, a proinflammatory cytokine and growth factor, is required for lymphocyte homeostasis. Intriguingly, the expression of IL-15 protein is tightly controlled by multiple posttranscriptional mechanisms. Here, we engineered a transgenic mouse to overexpress IL-15 by eliminating these posttranscriptional checkpoints. IL-15 transgenic mice have early expansions in natural killer (NK) and CD8+ T lymphocytes. Later, these mice develop fatal lymphocytic leukemia with a T-NK phenotype. These data provide novel evidence that leukemia, like certain other cancers, can arise as the result of chronic stimulation by a proinflammatory cytokine.

SUBMITTER: Fehniger TA

PROVIDER: S-EPMC2193336 | biostudies-literature | 2001 Jan

REPOSITORIES: biostudies-literature

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Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells.

Fehniger T A TA Suzuki K K Ponnappan A A VanDeusen J B JB Cooper M A MA Florea S M SM Freud A G AG Robinson M L ML Durbin J J Caligiuri M A MA

The Journal of experimental medicine 20010101 2

Inflammation likely has a role in the early genesis of certain malignancies. Interleukin (IL)-15, a proinflammatory cytokine and growth factor, is required for lymphocyte homeostasis. Intriguingly, the expression of IL-15 protein is tightly controlled by multiple posttranscriptional mechanisms. Here, we engineered a transgenic mouse to overexpress IL-15 by eliminating these posttranscriptional checkpoints. IL-15 transgenic mice have early expansions in natural killer (NK) and CD8+ T lymphocytes. ...[more]

PMID: 11208862

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Project description:ObjectiveGenetic associations imply a role for CD8+ T cells and the interleukin-23 (IL-23)/IL-17 axis in psoriatic arthritis (PsA) and other spondyloarthritides (SpA). IL-17A+CD8+ (Tc17) T cells are enriched in the synovial fluid (SF) of patients with PsA, and IL-17A blockade is clinically efficacious in PsA/SpA. This study was undertaken to determine the immunophenotype, molecular profile, and function of synovial Tc17 cells in order to elucidate their role in PsA/SpA pathogenesis.MethodsPeripheral blood (PB) and SF mononuclear cells were isolated from patients with PsA or other types of SpA. Cells were phenotypically, transcriptionally, and functionally analyzed by flow cytometry (n = 6-18), T cell receptor β (TCRβ) sequencing (n = 3), RNA-Seq (n = 3), quantitative reverse transcriptase-polymerase chain reaction (n = 4), and Luminex or enzyme-linked immunosorbent assay (n = 4-16).ResultsIL-17A+CD8+ T cells were predominantly TCRαβ+ and their frequencies were increased in the SF versus the PB of patients with established PsA (P < 0.0001) or other SpA (P = 0.0009). TCRβ sequencing showed that these cells were polyclonal in PsA (median clonality 0.08), while RNA-Seq and deep immunophenotyping revealed that PsA synovial Tc17 cells had hallmarks of Th17 cells (RORC/IL23R/CCR6/CD161) and Tc1 cells (granzyme A/B). Synovial Tc17 cells showed a strong tissue-resident memory T (Trm) cell signature and secreted a range of proinflammatory cytokines. We identified CXCR6 as a marker for synovial Tc17 cells, and increased levels of CXCR6 ligand CXCL16 in PsA SF (P = 0.0005), which may contribute to their retention in the joint.ConclusionOur results identify synovial Tc17 cells as a polyclonal subset of Trm cells characterized by polyfunctional, proinflammatory mediator production and CXCR6 expression. The molecular signature and functional profiling of these cells may help explain how Tc17 cells can contribute to synovial inflammation and disease persistence in PsA and possibly other types of SpA.

Project description:Many aged individuals develop monoclonal expansions of CD8 T cells. These expansions are derived from a CD8 memory T cell that outcompetes neighboring CD8 T cells. The molecular alterations within clonal expansions that confer this competitive advantage relative to other CD8 T cells remains unknown. These microarray experiments were designed to identify genes differentially expressed in age-associated expansions of CD8 memory T cells relative to polyclonal CD8 memory T cells found in the same aged mice. Subsequent analysis of these data identified two major types of clonal expansions, distinguished by expression level of integrin a4 mRNA and protein. Based on this classification, Expansion_rep1 belongs to the integrin a4 high subtype of clonal expansions. In contrast, reps 2, 4, and 5 belong to the integrin a4 low subtype of clonal expansions. Given the divergent biological properties of these two subtypes of clonal expansions, we have focused genes differentially expressed between Expansion_rep 2, 4, and 5 and their paired PolyclonalAged samples. Experiment Overall Design: A total of 8 samples were analyzed for gene expression using the Affymetrix mouse genome 430 2.0 microarray platform. The experimental samples of interest were age-associated clonal expansions of CD8 memory T cells. We purified four clonal expansions from four independent, aged mice (indicated as "Expansion" rep1 2, 3, 4). For each clonal expansion of CD8 memory T cells that was purified, there was a paired control in which polyclonal CD8 memory T cells were harvested from the same aged mouse (denoted as "PolyclonalAged" rep1, 2, 3, 4). These paired samples allow one to consider gene expression changes from mice which have undergone the same age-associated changes in biology. The predominant comparison this study focused on was changes in gene expression between age-associated clonal expansions of CD8 memory T cells and their paired, polyclonal CD8 memory T cells. A total of 4 of these pairs were collected.

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Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells.

Publications

Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells.

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