Constitutive CD8 expression drives innate CD8+ T cell differentiation via induction of iNKT2 subset
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE132059 | GEO | 2019/06/01
REPOSITORIES: GEO
Similar Datasets
Project description:Constitutive CD8 expression drives innate CD8+ T cell differentiation via induction of iNKT2 subset
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Project description:Temporal down-regulation of the CD8 co-receptor after receiving positive-selection signals has been proposed to serve as an important determinant to segregate helper versus cytotoxic lineages by generating differences in the duration of TCR signaling between MHC-I and MHC-II selected thymocytes. By contrast, little is known about whether CD8 also modulates TCR signaling engaged by the non-classical MHC-I-like molecule, CD1d, during development of invariant natural killer T (iNKT) cells. Here, we show that constitutive transgenic CD8 expression resulted in enhanced differentiation of innate memory-like CD8+ thymocytes in both a cell-intrinsic and cell-extrinsic manner, the latter being accomplished by an increase in the IL-4-producing iNKT2 subset. Skewed iNKT2 differentiation requires cysteine residues in the intracellular domain of CD8α that are essential for transmitting cellular signaling. Collectively, these findings shed a new light on the relevance of CD8 down-regulation in shaping the balance of iNKT-cell subsets by modulating TCR signaling.
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Project description:Serotonin deficiency from constitutive SKN-1 activation drives pathogen apathy
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Project description:When an organism encounters a pathogen, the host innate immune system is activated to defend against pathogen colonization and the toxic xenobiotics produced. C. elegans employ multiple defense systems to ensure survival when exposed to Pseudomonas aeruginosa (PA14) including activation of the cytoprotective transcription factor SKN-1/NRF2. Although wildtype C. elegans quickly learn to avoid pathogens, here we describe a peculiar apathy to PA14 in animals with constitutive activation of SKN-1, whereby animals choose not to leave while continuing to feed on the pathogen even when a non-pathogenic food option is available. Although lacking the urgency to escape the infectious environment, animals with constitutive SKN-1 activity are not oblivious to the presence of the pathogen and display a typical intestinal distension from PA14 colonization and eventual demise, but surprisingly, fail to learn to avoid pathogen with training. SKN-1 activation, specifically in neurons and intestinal tissues, orchestrates a unique transcriptional program which leads to defects in serotonin signaling from both neurons and non-neuronal tissues that drives the pathogen apathy behavior and pleiotropic responses to selective serotonin reuptake inhibitors (SSRIs). Taken together, our work reveals new insights into how animals perceive environmental pathogens and subsequently alter behavior and cellular programs to promote survival.
2024-08-15 | GSE251677 | GEO
Project description:Innate memory phenotype (IMP) CD8+ T cells are non-conventional αβ T cells exhibiting features of innate immune cells, and are significantly increased in the absence of non-receptor tyrosine kinase ITK. Their developmental path and function are not clear, particularly whether they can contribute to antigen specific responses. We found that WT bone marrow gives rise to IMP CD8+ T cells in irradiated MHCI-/- recipients, resembling those in Itk-/- mice determined by expression of surface markers. However, CD8+ T cells share similar expression of memory markers. We used microarrays to compare the global programme of gene expression to determine whether the CD8+ T cells selected by hematopoietic MHCI are IMP CD8+ T cells as observed in the absence of ITK, or the result of homeostatic expansion of T cell contamination in the donor bone marrow. Through analysis of global gene expression correlation and differential expression, we determined that hematopoietic MHCI dependent IMP CD8+ T cells generated in irradiated MHCI-/- recipients, resemble those in Itk-/- mice, but distinct from CD8+ T cells derived via homeostatic proliferation. Cell sorting was performed using a FACSAria Cell Sorter (BD Biosciences, San Diego, CA). IMP CD8+ T cells (TCRβ+CD8α+CD44hi) were sorted from splenocytes of WT→MHCI-/- chimeras 8 weeks post transplantation and 8-week old Itk-/- mice. To generate HP cells, naïve CD8+ T cells (TCRβ+CD8α+CD44lo) were sorted and injected into Rag1-/- recipients (0.5 million /mouse, retro-orbital injection), followed by sorting of TCRβ+CD8α+ splenocytes 8 weeks post adoptive transfer. We sought to compare cells with the same gender and age, thus all donors were female, and ages (absolute age for Itk null and age post transfer for chimeras and HP model) were 8 weeks.
2013-02-19 | E-GEOD-41482 | biostudies-arrayexpress
Project description:CD8(+) T cells develop increased sensitivity following Ag experience, and differences in sensitivity exist between T cell memory subsets. How differential TCR signaling between memory subsets contributes to sensitivity differences is unclear. We show in mouse effector memory T cells (TEM) that >50% of lymphocyte-specific protein tyrosine kinase (Lck) exists in a constitutively active conformation, compared with <20% in central memory T cells (TCM). Immediately proximal to Lck signaling, we observed enhanced Zap-70 phosphorylation in TEM following TCR ligation compared with TCM Furthermore, we observed superior cytotoxic effector function in TEM compared with TCM, and we provide evidence that this results from a lower probability of TCM reaching threshold signaling owing to the decreased magnitude of TCR-proximal signaling. We provide evidence that the differences in Lck constitutive activity between CD8(+) TCM and TEM are due to differential regulation by SH2 domain-containing phosphatase-1 (Shp-1) and C-terminal Src kinase, and we use modeling of early TCR signaling to reveal the significance of these differences. We show that inhibition of Shp-1 results in increased constitutive Lck activity in TCM to levels similar to TEM, as well as increased cytotoxic effector function in TCM Collectively, this work demonstrates a role for constitutive Lck activity in controlling Ag sensitivity, and it suggests that differential activities of TCR-proximal signaling components may contribute to establishing the divergent effector properties of TCM and TEM. This work also identifies Shp-1 as a potential target to improve the cytotoxic effector functions of TCM for adoptive cell therapy applications.
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Project description:Carbon source availability drives nutrient utilization in CD8+ T cells
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Project description:CD4 CD8 double positive (DP) thymocytes progressively shut down Notch signaling after β-selection allowing progression of the DP program and positive selection of conventional CD4 and CD8 single positive T cells. In contrast, innate CD8+ T cells are selected from DP precursors shortly after β-selection. Here, we investigated whether notch signaling is required for the initiation of the innate T cell developmental program upon TCR engagement. We show that, after β-selection, Notch activation limits progression to late DP cells and favors the development of TCRαβ/CD3 expressing CD8dim early DP progenitors. TCR engagement in these Notch dependent TCRαβ+ early DP precursors does not induce prominent apoptosis, but rather induces T-bet expression by an mTOR-dependent mechanism. Our findings indicate that Notch signaling drives the launch of an innate effector program in response to TCR agonist selection in the thymus.
2019-09-05 | GSE100519 | GEO
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.
2023-11-27 | GSE241145 | GEO
Project description:Poly(ADP ribose) polymerase inhibitors (PARPi) have efficacy in triple negative breast (TNBC) and ovarian cancers (OCs) harboring BRCA mutations, generating homologous recombination deficiencies (HRDs). DNA methyltransferase inhibitors (DNMTi) increase PARP trapping and reprogram the DNA damage response to generate HRD, sensitizing BRCA-proficient cancers to PARPi. We now define the mechanisms through which HRD is induced in BRCA-proficient TNBC and OC. DNMTi in combination with PARPi up-regulate broad innate immune and inflammasome-like signaling events, driven in part by stimulator of interferon genes (STING), to unexpectedly directly generate HRD. This inverse relationship between inflammation and DNA repair is critical, not only for the induced phenotype, but also appears as a widespread occurrence in The Cancer Genome Atlas datasets and cancer subtypes. These discerned interactions between inflammation signaling and DNA repair mechanisms now elucidate how epigenetic therapy enhances PARPi efficacy in the setting of BRCA-proficient cancer. This paradigm will be tested in a phase I/II TNBC clinical trial.
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