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The transcription factor Tcf1 ensures the development and cytotoxic function of NK cells by limiting the expression of Granzymes [ChIP-Seq]

ABSTRACT: The transcription factor Tcf1 plays an essential role for the development of NK cells, however, its precise role for NK cell development, maturation and function is poorly understood. Here we show that distinct domains of Tcf1 direct bone marrow progenitors towards the NK cell lineage and mediate lineage commitment and NK cell expansion, and that Tcf1 downregulation is required for terminal NK cell maturation. Impaired NK cell development in the absence of Tcf1 is explained by increased cell death due to excessive expression of Granzyme family proteins, which results in NK cell self-destruction. In addition, excessive Granzyme B expression leads to target cell induced NK cell death and consequently reduced target cell killing by NK cells lacking Tcf1. Mechanistically, Tcf1 prevents excessive Granzyme B expression by binding to a newly identified enhancer element upstream of the Granzyme B locus. These data identify an unexpected requirement to limit the expression of cytotoxic effector molecules for lymphocyte development.

ORGANISM(S): Mus musculus

PROVIDER: GSE92710 | GEO | 2017/08/23

SECONDARY ACCESSION(S): PRJNA358408

REPOSITORIES: GEO

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Project description:The HMG-box factor Tcf1 is required during T-cell development in the thymus and mediates the nuclear response to Wnt signals. Tcf1-/- mice have previously been characterized and show developmental blocks at the CD4-CD8- double negative (DN) to CD4+CD8+ double positive transition. Due to the blocks in T-cell development, Tcf1-/- mice normally have a very small thymus. Unexpectedly, a large proportion of Tcf1-/- mice spontaneously develop thymic lymphomas with 50% of mice developing a thymic lymphoma/leukemia at the age of 16 wk. These lymphomas are clonal, highly metastatic, and paradoxically show high Wnt signaling when crossed with Wnt reporter mice and have high expression of Wnt target genes Lef1 and Axin2. In wild-type thymocytes, Tcf1 is higher expressed than Lef1, with a predominance of Wnt inhibitory isoforms. Loss of Tcf1 as repressor of Lef1 leads to high Wnt activity and is the initiating event in lymphoma development, which is exacerbated by activating Notch1 mutations. Thus, Notch1 and loss of Tcf1 functionally act as collaborating oncogenic events. Tcf1 deficiency predisposes to the development of thymic lymphomas by ectopic up-regulation of Lef1 due to lack of Tcf1 repressive isoforms and frequently by cooperating activating mutations in Notch1. Tcf1 therefore functions as a T-cell‚Äìspecific tumor suppressor gene, besides its established role as a Wnt responsive transcription factor. Thus, Tcf1 acts as a molecular switch between proliferative and repressive signals during T-lymphocyte development in the thymus. Using the Tcf1-/- DeltaVII/DeltaVII knockout mouse (Verbeek et al. Nature 1995), thymocytes of 17 mice (5 control Tcf+/-, 4 Tcf-/- and 8 Tcf-/- with thymic lymphoma) were homogenized for RNA isolation using Qiagen RNeasy minicolumns. The quantity and quality of total RNA was determined using spectrophotometry (Nanodrop) and an Agilent Bioanalyzer. One ¬µg of RNA was used to generate cRNA using Affymetrix One cycle cDNA synthesis kit (Affymetrix, Santa Clara, CA, USA), after which the samples were biotinylated using an Affymetrix IVT labeling kit (Affymetrix). The samples were hybridized overnight at 42¬?C to GeneChip mouse genome 430 2.0 Arrays (Affymetrix). Washing and staining steps were performed on a Fluidics station 450, and the Genechips were scanned using a GeneChip scanner 3000 (Affymetrix) at the Department of Immunology, Erasmus Medical Center. Raw data were normalized and summarized using Robust Multichip Average (RMA) method. The experiment consists of 5 control Tcf+/- thymi, 4 Tcf-/- thymi and 8 Tcf-/- thymus samples with thymic lymphoma.

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The transcription factor Tcf1 ensures the development and cytotoxic function of NK cells by limiting the expression of Granzymes [ChIP-Seq]

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