Browse
Submit Data
Databases
API
Help

Dataset Information

2 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CD117 (c-Kit) Is Expressed During CD8+ T Cell Priming and Stratifies Sensitivity to Apoptosis According to Strength of TCR Engagement.

ABSTRACT: CD117 (cKit) is the receptor for stem cell factor (SCF) and plays an important role in early haemopoiesis. We show that CD117 is also expressed following priming of mature human CD8+ T cells in vitro and is detectable following primary infection in vivo. CD117 expression is mediated through an intrinsic pathway and is suppressed by IL-12. Importantly, the extent of CD117 expression is inversely related to the strength of the activating stimulus and subsequent engagement with cell-bound SCF markedly increases susceptibility to apoptosis. CD117 is therefore likely to shape the pattern of CD8+ T cell immunodominance during a primary immune response by rendering cells with low avidity for antigen more prone to apoptosis. Furthermore, CD117+ T cells are highly sensitive to apoptosis mediated by galectin-1, a molecule commonly expressed within the tumor microenvironment, and CD117 expression may therefore represent a novel and potentially targetable mechanism of tumor immune evasion.

SUBMITTER: Frumento G

PROVIDER: S-EPMC6428734 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

TCR Signal Strength and Antigen Affinity Regulate CD8+ Memory T Cells.

Project description:CD8+ T cells play a critical role in adaptive immunity, differentiating into CD8+ memory T cells that form the basis of protective cellular immunity. Vaccine efficacy is attributed to long-term protective immunity, and understanding the parameters that regulate development of CD8+ T cells is critical to the design of T cell-mediated vaccines. We show in this study using mouse models that two distinct parameters, TCR signal strength (regulated by the tyrosine kinase ITK) and Ag affinity, play important but separate roles in modulating the development of memory CD8+ T cells. Unexpectedly, our data reveal that reducing TCR signal strength along with reducing Ag affinity for the TCR leads to enhanced and accelerated development of CD8+ memory T cells. Additionally, TCR signal strength is able to regulate CD8+ T cell effector cytokine R production independent of TCR Ag affinity. Analysis of RNA-sequencing data reveals that genes for inflammatory cytokines/cytokine receptors are significantly altered upon changes in Ag affinity and TCR signal strength. Furthermore, our findings show that the inflammatory milieu is critical in regulating this TCR signal strength-mediated increase in memory development, as both CpG oligonucleotide treatment or cotransfer of wild-type and Itk-/- T cells eliminates the observed increase in memory cell formation. These findings suggest that TCR signal strength and Ag affinity independently contribute to CD8+ memory T cell development, which is modulated by inflammation, and suggest that manipulating TCR signal strength along with Ag affinity, may be used to tune the development of CD8+ memory T cells during vaccine development.

| S-EPMC8104072 | biostudies-literature

Impaired functional responses in follicular lymphoma CD8+TIM-3+ T lymphocytes following TCR engagement.

Project description:Upregulation of T cell immunoglobulin-3 (TIM-3) has been associated with negative regulation of the immune response in chronic infection and cancer, including lymphoma. Here, we investigated the possible correlation between TIM-3 expression by ex vivo cytotoxic T cells (CTL) from follicular lymphoma (FL) biopsies and their functional unresponsiveness that could limit the favorable impact of CTL on disease progression. We report a high percentage of CD8+TIM-3+T cells in lymph nodes of FL patients. When compared to their CD8+TIM-3- counterparts, CD8+TIM-3+ T cells exhibited defective cytokine production following TCR engagement. Furthermore, CD8+TIM-3+ T cells display ex vivo markers of lytic granule release and remain unresponsive to further TCR-induced activation of the lytic machinery. Although confocal microscopy showed that TIM-3 expression on CD8+ T cells correlated with minor alterations of immunological synapse, a selective reduction of ERK signaling in CD8+TIM-3+T cells was observed by phospho-flow analysis. Finally, short relapse-free survival despite rituximab(R)-chemotherapy was observed in patients with high content of TIM-3+ cells and a poor infiltrate of granzyme B+ T cells in FL lymph nodes. Together, our data indicate that, besides selective TCR early signaling defects, TIM-3 expression correlates with unresponsiveness of ex vivo CD8+ T cells in FL. They show that scores based on the combination of exhaustion and cytolytic markers in FL microenvironment might be instrumental to identify patients at early risk of relapses following R-chemotherapy.

| S-EPMC5135226 | biostudies-literature

Assessment of TCR signal strength of antigen-specific memory CD8+ T cells in human blood.

Project description:Assessment of the quality and the breadth of antigen (Ag)-specific memory T cells in human samples is of paramount importance to elucidate the pathogenesis and to develop new treatments in various diseases. T-cell receptor (TCR) signal strength, primarily controlled by TCR affinity, affects many fundamental aspects of T-cell biology; however, no current assays for detection of Ag-specific CD8+ T cells can assess their TCR signal strength in human samples. Here, we provide evidence that interferon regulatory factor 4 (IRF4), a transcription factor rapidly upregulated in correlation with TCR signal strength, permits the assessment of the TCR signal strength of Ag-specific CD8+ T cells in human peripheral blood mononuclear cells (PBMCs). Coexpression of IRF4 and CD137 sensitively detected peptide-specific CD8+ T cells with extremely low background in PBMCs stimulated for 18 hours with MHC class I peptides. Our assay revealed that human memory CD8+ T cells with high-affinity TCRs have an intrinsic ability to highly express CD25. Furthermore, HIV-specific CD8+ T cells in chronic HIV+ subjects were found to display primarily low-affinity TCRs with low CD25 expression capacity. Impairment in the functions of HIV-specific CD8+ T cells might be associated with their suboptimal TCR signals, as well as impaired responsiveness to interleukin-2.

| S-EPMC6650739 | biostudies-literature

TCR-α/β CD4- CD8- double negative T cells arise from CD8+ T cells.

Project description:The cellular origin of CD4- CD8- (double negative, DNT) TCR-α/β+ T cells remains unknown. Available evidence indicates that they may derive from CD8+ T cells, but most published data have been obtained using cells that bear an invariant transgenic T cell receptor that recognizes an Ag that is not present in normal mice. Here, we have used complementary fate mapping and adoptive transfer experiments to identify the cellular lineage of origin of DNT cells in wild-type mice with a polyclonal T cell repertoire. We show that TCR-α/β+ DNT cells can be traced back to CD8+ and CD4+ CD8+ double positive cells in the thymus. We also demonstrate that polyclonal DNT cells generated in secondary lymphoid organs proliferate upon adoptive transfer and can regain CD8 expression in lymphopenic environment. These results demonstrate the cellular origin of DNT cells and provide a conceptual framework to understand their presence in pathological circumstances.

| S-EPMC8118277 | biostudies-literature

Innate-like NKp30+CD8+ T cells armed with TCR/CAR target tumor heterogeneity.

Project description:Intratumoral heterogeneity is frequently associated with tumor immune escape, with MHC-class I and antigen expression loss rendering tumor cells invisible to T cell killing, representing a major challenge for the design of successful adoptive transfer protocols for cancer immunotherapy. While CD8+ T cell recognition of tumor cells is based on the detection of MHC-peptide complexes via specific T cell receptors (TCRs), Natural Killer (NK) cells detect tumor-associated NK ligands by an array of NK receptors. We have recently identified a population of innate-like CD8+ T cells marked by the expression of NKp30, a potent natural cytotoxicity activating NK receptor, whose tumor ligand, B7H6, is frequently upregulated on several cancer types. Here, we harnessed the dual-recognition potential of NKp30+CD8+ T cells, by arming these cells with TCRs or chimeric antigen receptors (CARs) targeting Epidermal Growth Factor Receptor 2 (ErbB2, or HER2), a tumor-associated target overexpressed in several malignancies. HER2-specific NKp30+CD8+ T cells killed not only HER2-expressing target cell lines, but also eliminated tumor cells in the absence of MHC-class I or antigen expression, making them especially effective in eliminating heterogeneous tumor cell populations. Our results show that NKp30+CD8+ T cells equipped with a specific TCR or CAR display a dual capacity to recognize and kill target cells, combining the anti-tumor activity of both CD8+ T and NK cells. This dual-recognition capacity allows these effector cells to target tumor heterogeneity, thus improving therapeutic strategies against tumor escape.

| S-EPMC8758178 | biostudies-literature

Helpless Priming Sends CD8+ T Cells on the Road to Exhaustion.

Project description:Persistent antigen exposure in chronic infection and cancer has been proposed to lead to cytotoxic T lymphocyte (CTL) "exhaustion", i.e., loss of effector function and disease control. Recent work identifies a population of poorly differentiated TCF-1+PD-1+ CD8+ T cells as precursors of the terminally exhausted CTL pool. These "predysfunctional" CTLs are suggested to respond to PD-1 targeted therapy by giving rise to a pool of functional CTLs. Supported by gene expression analyses, we present a model in which lack of CD4+ T cell help during CD8+ T cell priming results in the formation of predysfunctional CTLs. Our model implies that predysfunctional CTLs are formed during priming and that the remedy for CTL dysfunction is to provide "help" signals for generation of optimal CTL effectors. We substantiate that this may be achieved by engaging CD4+ T cells in new CD8+ T cell priming, or by combined PD-1 blocking and CD27 agonism with available immunotherapeutic antibodies.

| S-EPMC7573232 | biostudies-literature

TNIK signaling imprints CD8+ T cell memory formation early after priming.

Project description:Co-stimulatory signals, cytokines and transcription factors regulate the balance between effector and memory cell differentiation during T cell activation. Here, we analyse the role of the TRAF2-/NCK-interacting kinase (TNIK), a signaling molecule downstream of the tumor necrosis factor superfamily receptors such as CD27, in the regulation of CD8+ T cell fate during acute infection with lymphocytic choriomeningitis virus. Priming of CD8+ T cells induces a TNIK-dependent nuclear translocation of β-catenin with consecutive Wnt pathway activation. TNIK-deficiency during T cell activation results in enhanced differentiation towards effector cells, glycolysis and apoptosis. TNIK signaling enriches for memory precursors by favouring symmetric over asymmetric cell division. This enlarges the pool of memory CD8+ T cells and increases their capacity to expand after re-infection in serial re-transplantation experiments. These findings reveal that TNIK is an important regulator of effector and memory T cell differentiation and induces a population of stem cell-like memory T cells.

| S-EPMC7118140 | biostudies-literature

Thymic progenitors of TCR??+ CD8?? intestinal intraepithelial lymphocytes require RasGRP1 for development.

Project description:Strong T cell receptor (TCR) signaling largely induces cell death during thymocyte development, whereas weak TCR signals induce positive selection. However, some T cell lineages require strong TCR signals for differentiation through a process termed agonist selection. The signaling relationships that underlie these three fates are unknown. RasGRP1 is a Ras activator required to transmit weak TCR signals leading to positive selection. Here, we report that, despite being dispensable for thymocyte clonal deletion, RasGRP1 is critical for agonist selection of TCR??+CD8?? intraepithelial lymphocyte (IEL) progenitors (IELps), even though both outcomes require strong TCR signaling. Bim deficiency rescued IELp development in RasGRP1-/- mice, suggesting that RasGRP1 functions to promote survival during IELp generation. Additionally, expression of CD122 and the adhesion molecules ?4?7 and CD103 define distinct IELp subsets with differing abilities to generate TCR??+CD8?? IEL in vivo. These findings demonstrate that RasGRP1-dependent signaling underpins thymic selection processes induced by both weak and strong TCR signals and is differentially required for fate decisions derived from a strong TCR stimulus.

| S-EPMC5551581 | biostudies-literature

TGFβ limits Myc-dependent TCR-induced metabolic reprogramming in CD8+ T cells.

Project description:T cell activation is dependent upon the integration of antigenic, co-stimulatory and cytokine-derived signals and the availability and acquisition of nutrients from the environment. Furthermore, T cell activation is accompanied by reprogramming of cellular metabolism to provide the energy and building blocks for proliferation, differentiation and effector function. Transforming growth factor β (TGFβ) has pleiotropic effects on T cell populations, having both an essential role in the maintenance of immune tolerance but also context-dependent pro-inflammatory functions. We set out to define the mechanisms underpinning the suppressive effects of TGFβ on mouse CD8+ T cell activation. RNA-sequencing analysis of TCR-stimulated T cells determined that Myc-regulated genes were highly enriched within gene sets downregulated by TGFβ. Functional analysis demonstrated that TGFβ impeded TCR-induced upregulation of amino acid transporter expression, amino acid uptake and protein synthesis. Furthermore, TCR-induced upregulation of Myc-dependent glycolytic metabolism was substantially inhibited by TGFβ treatment with minimal effects on mitochondrial respiration. Thus, our data suggest that inhibition of Myc-dependent metabolic reprogramming represents a major mechanism underpinning the suppressive effects of TGFβ on CD8+ T cell activation.

| S-EPMC9360539 | biostudies-literature

PSGL-1 attenuates early TCR signaling to suppress CD8+ T cell progenitor differentiation and elicit terminal CD8+ T cell exhaustion.

Project description:PSGL-1 (P-selectin glycoprotein-1) is a T cell-intrinsic checkpoint regulator of exhaustion with an unknown mechanism of action. Here, we show that PSGL-1 acts upstream of PD-1 and requires co-ligation with the T cell receptor (TCR) to attenuate activation of mouse and human CD8+ T cells and drive terminal T cell exhaustion. PSGL-1 directly restrains TCR signaling via Zap70 and maintains expression of the Zap70 inhibitor Sts-1. PSGL-1 deficiency empowers CD8+ T cells to respond to low-affinity TCR ligands and inhibit growth of PD-1-blockade-resistant melanoma by enabling tumor-infiltrating T cells to sustain an elevated metabolic gene signature supportive of increased glycolysis and glucose uptake to promote effector function. This outcome is coupled to an increased abundance of CD8+ T cell stem cell-like progenitors that maintain effector functions. Additionally, pharmacologic blockade of PSGL-1 curtails T cell exhaustion, indicating that PSGL-1 represents an immunotherapeutic target for PD-1-blockade-resistant tumors.

| S-EPMC10403047 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data