Transcriptional Regulation by NFATc1 in CD8+ T cells [RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE98725 | GEO | 2017/07/03
SECONDARY ACCESSION(S): PRJNA386036
REPOSITORIES: GEO
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Project description:Cytotoxic T Lymphocytes (CTLs) are effector CD8+T cells that eradicate infected and malignant cells from organism. We analyze the role of the transcription factor NFATc1 in activation and cytotoxicity of murine CD8+ T lymphocytes
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Project description:A plethora of data supports a major role of CD4+ and CD8+ T lymphocytes for the initiation, progression and maintenance of allergic contact dermatitis (ACD). However, in-depth understanding of the underlying molecular mechanisms is still limited. NFATc1 , a central component of the Ca++-Calcineurin-NFAT-signalling network, plays an essential role in T cell activation. We therefore investigated its impact on contact hypersensitivity (CHS), the mouse model for ACD. The CHS response to 2,4,6-trinitrochlorobenzene (TNCB) was diminished in Nfatc1fl/flxCd4-cre mice (Nfatc1-/-) as compared to wild-type (WT) animals and associated with a lower percentage of interleukin (IL)17-producing CD8+T (Tc17) cells in both inflamed skin and draining lymph nodes (dLN). In vitro Tc17 polarization assays revealed that Nfatc1-/- CD8+ T cells have a reduced capacity to polarize into Tc17 cells. Applying single-cell RNA sequencing, we realized that NFATc1 controls the T cell differentiation fate. In the absence of NFATc1, CD8+ T cells favour the development of Interferon (IFN)-g-secreting CD8+ T (Tc1) lymphocytes while in its presence they turn into Tc17 cells. Finally, we showed the adoptive transfer of TNCB-sensitized WT CD8+T cells rescued tThe CHS response could be rescued in naïve Nfatc1-/-mice by adoptive transfer of TNCB-sensitized WT CD8+T cells. Our data demonstrate that NFATc1 acts as a molecular switch controllcontrolsing the development of Tc17 cells and can be used as a target to alleviate surveilling CD8+T cell-mediated CHS responses.
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Project description:Acquisition of effector properties is a key step in the generation of cytotoxic T lymphocytes (CTLs). Here we show that inflammatory signals regulate Dicer expression in CTL, and that deletion or depletion of Dicer in mouse or human activated CD8+ T cells causes upregulation of perforin, granzyme and effector cytokines. Genome-wide analysis of miRNA changes induced by exposure of differentiating CTLs to IL-2 and inflammatory signals identifies miR-139 and miR-150 as components of a miRNA network that controls perforin, eomesodermin (Eomes) and IL-2Ra expression in differentiating CTLs and whose activity is modulated by IL-2, inflammation and antigenic stimulation. Overall our data show that strong IL-2R and inflammatory signals act through Dicer and miRNAs to control the cytolytic program and other aspects of effector CTL differentiation. Comparison of control and Dicer knock-out CTLs differentiated in vitro; Comparison of wild type CTLs differentiated in vitro with or without inflammatory stimuli; Comparison of effector and memory precursor CTLs isolated from mice infected with LCMV-Armstrong
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Project description:We wished to examine early transcriptional changes that occur after TCR engagement in CD8+ cytotoxic T lymphocytes (CTLs). To this end, we differentiated effector CTLs from OTI TCR transgenic mice for 7 days in vitro and then stimulated them with anti-CD3 for various times before lysing for RNA-seq. Results demonstrated significant transcriptional changes starting from 20 minutes. After 60 minutes, upregulated genes were most enriched for cytokines and transcriptional machinery.
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Project description:Bach2 codes for a transcriptional regulator exerting major influences on T cell mediated immune regulation. Effector CTLs derived from in vitro activation of murine CD8+ T cells showed increased proliferative and cytolytic capacity in the absence of BACH2. Before activation, BACH2-deficient CD8+ T cells had a higher abundance of memory and reduced abundance of naïve cells compared to wild-type. CTLs derived from central memory T cells were more potently cytotoxic than those derived from naïve T cells, but even within separated subsets, BACH2-deficiency conferred a cytotoxic advantage. Immunofluorescence and electron microscopy revealed larger granules in BACH2-deficient compared to wild-type CTLs, and proteomic analysis showed an increase in granule content, including perforin and granzymes. Thus, the enhanced cytotoxicity observed in effector CTLs lacking BACH2 arises not only from differences in their initial differentiation state but also inherent production of enlarged cytolytic granules. These results demonstrate how a single gene deletion can produce a CTL super-killer.
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Project description:In lymphocytes, NFATc1 is the most prominent NFAT transcription factor which play a crucial role in the fate and activity of peripheral T and B cells. NFATc1 is synthesized in two prominent isoforms, the inducible short isoform NFATc1/aA and the constitutively expressed long isoform NFATc1/C. Several lines of evidence suggested that both isoforms differ markedly in their function. It was speculated that NFATc1/aA supports the proliferation and survival of lymphocytes, whereas NFATc1/C should support apoptosis and anergy induction. To proof this hypothesis we established WEHI 231 B lymphoma cells that stably (over-) express either NFATc1/aA or NFATc1/C. In preliminary experiments we could should that WEHI cells overexpressing NFATc1/aA were protected against apoptosis induction, while cells overexpressing NFATc1/C should a higher apoptosis rate. Transcriptom analysis of WEHI-231 cells overexpressing either NFATc1/aA or NFATc1/C were performed, along with a control group of WEHI-231 cells overexpressing the E.coli enzyme BirA Ligase (which is also present in all target cell lines since for further molecular assays the NFATc1 proteins were expressed as chimeric protein containing C-terminal bio-tags. The experimental results obtained indicate that the both NFATc1 proteins, NFATc1/aA and NFATc1/C, differ tremendously in their transcriptional properties.
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Project description:CD8+ cytotoxic T lymphocytes (CTLs) play a major role in defense against intracellular pathogens, and their functions are specified by antigen recognition and innate cytokines. While effector CTLs eliminate the infection, a small population of memory cells are retained that yields more rapid and robust response upon re-infection. Antigen presenting cells secrete an array of innate cytokines including IL-12 and IFN-α after recognition of pathogens. Both IL-12 and IFN-α have been shown to act as the third signal regulating the development of CTLs. We have shown that these two cytokines have a non-redundant effect in generation of human effector CTL. IL-12 alone is sufficient for effector CTL genesis marked by IFN-γ and TNF-α production, as well as increased cytolytic activity. Even in the presence of IFN-α, IL-12 programs CTLs that express the chemokine receptor CXCR3 and effector cytokines. Using microarray analysis we have investigated how IL-12 and IFN-α differentially regulate the genetic programming pathways that give rise to effector CTLs among multiple human donors. We have also analyzed the gene expression patterns of cells sorted from healthy human peripheral blood that display surface markers of effector memory CTL (designated as ex vivo) samples. 5 healthy human donor samples were used for the in vitro cultures. For each donor the CFSE labeled cells (CD8+CD45RA+) were cultured in the presence of neutralized, IL-12, IFN-a, and IL-12+IFN-a conditions and plate-bound anti-CD3+anti-CD28 for 3.5 days. Total RNA from CFSEhi (Undiv) and CFSElo (Div) sorted cells were used for Illumina Bead Array. 4 healthy human donor samples were used for the ex vivo samples. Total RNA was collected from FACS sorted CD8+CCR7hiCXCR3lo and CD8+CCR7loCXCR3hi cells without any stimulation.
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Project description:Transcriptional Regulation by NFATc1 in CD8+ T cells
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Project description:Cancer immunotherapies boost antitumor immunity and improve the survival of cancer patients. V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an immune 20 checkpoint target but presents elusive signaling mechanisms. We report a novel VISTA binding partner, Leucine-Rich Repeats and Immunoglobulin Like Domains 1 (LRIG1), which acts as an inhibitory receptor by engaging VISTA and suppressing T cell receptor signaling pathways. Mice with T cell-specific LRIG1 deletion developed superior antitumor T cell responses. Mechanistically, LRIG1-deficient tumor-specific CD8+ cytotoxic T cells (CTLs) exhibited longer 25 persistence due to improved expansion and survival and greater effector function. Sustained tumor control was also associated with a reduction of quiescent CTLs (TCF1+ CD62Lhi PD-1low) and a reciprocal increase in progenitor and memory-like CTLs (TCF1+ PD-1+). In human melanoma, an elevated LRIG1 expression on tumor-infiltrating CD8+ CTLs correlated with resistance to immunotherapies. Taken together, these results delineate the role of LRIG1 as an inhibitory 30 immune checkpoint receptor and propose a rationale for targeting the VISTA/LRIG1 axis for cancer immunotherapy.
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