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GSE65660
Mus musculus
12 Downloadable Samples
Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
TFH and Th1 cells generated after viral or intracellular bacterial infections are critical for the control of infections and the development of immunological memories. However, the mechanisms that govern the choice of activated CD4 T cells to the two alternative fates remain unclear. Here, we found that reciprocal expression of TCF1 and Blimp1 between viral-specific TFH and Th1 cells started early after infection. TCF1 was intrinsically required for the differentiation of TFH cells. In the absence of TCF1, TFH cells failed to maintain their transcriptional and metabolic signatures, distinct from those in Th1 cells. Mechanistically, TCF1 functioned through forming negative feedback loops with IL-2 and Blimp1 signaling. Thus, we have demonstrated an essential role of TCF1 in TFH-cell differentiation.
Publication Title
TCF1 Is Required for the T Follicular Helper Cell Response to Viral Infection.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 32 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Mouse CD8+ T cells affected by ID3 (Inhibitor of DNA binding 3) display patterns of gene expression suggesting enhanced persistance and survival. In this study, we identified genes differentially expressed between ID32a transduced and mock transduced, and ID32a knockout and wild type mouse CD8+ T cells. Most prominent functions of differentially expressed genes include DNA replication-associated repair, maintenance of chromosome stability and mitotic cell divison machinery. Overall, these data suggest that ID3 acts in favor of maintained survival in CD8+ mouse T cells.
Publication Title
Repression of the DNA-binding inhibitor Id3 by Blimp-1 limits the formation of memory CD8+ T cells.
Sample Metadata Fields
Treatment
View Samples- Mus musculus
- 12 Downloadable Samples
Illumina Genome Analyzer
Description
Our data represents the first analysis of histone methyltransferase Ezh2 regulated transcriptomes in mouse CD8 T cells. Overall design: Naïve and in vitro TCR stimulated CD8 T cell mRNA profiles of Pmel-1 wild type (WT) and Ezh2-/- mice were generated by deep sequencing, in triplicate, using Illumina.
Publication Title
Ezh2 phosphorylation state determines its capacity to maintain CD8<sup>+</sup> T memory precursors for antitumor immunity.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Long-lived, self-renewing, multipotent T memory stem cells (TSCM) can trigger profound and sustained tumor regression but their rareness poses a major hurdle to their clinical application. Presently, clinically compliant procedures to generate relevant numbers of this T cell population are undefined. Here, we provide a strategy for deriving large numbers of clinical grade tumor-redirected TSCM cells starting from nave precursors. CD8+CD62L+CD45RA+ nave T cells enriched by streptamer-based serial positive selection were activated by CD3/CD28 engagement in the presence of IL-7, IL-21 and the glycogen synthase-3 inhibitor TWS119, and genetically engineered to express a CD19-specific chimeric antigen receptor (CD19-CAR). These conditions allowed for the generation of CD19-CAR modified TSCM cells that were phenotypically, functionally and transcriptomically equivalent to their naturally occurring counterpart. Compared with T cell products currently under clinical investigation, CD19-CAR modified TSCM cells exhibit enhanced metabolic fitness, persistence and anti-tumor activity against systemic acute lymphoblastic leukemia xenografts. Based on these findings, we have initiated a phase 1 clinical study to evaluate the activity of CD19-CAR modified TSCM in patients with B-cell malignancies refractory to prior allogeneic hematopoietic stem cell transplantation.
Publication Title
Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies.
Sample Metadata Fields
Subject
View Samples- Mus musculus
- 11 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Effector cells for adoptive immunotherapy can be generated by in vitro stimulation of nave or memory subsets of CD8+ T cells. While the characteristics of CD8+ T cell subsets are well defined, the heritable influence of those populations on their effector cell progeny is not well understood. We studied effector cells generated from nave or central memory CD8+ T cells and found that they retained distinct gene expression signatures and developmental programs. Effector cells derived from central memory cells tended to retain their CD62L+ phenotype, but also to acquire KLRG1, an indicator of cellular senescence. In contrast, the effector cell progeny of nave cells displayed reduced terminal differentiation, and, following infusion, they displayed greater expansion, cytokine production, and tumor destruction. These data indicate that effector cells retain a gene expression imprint conferred by their nave or central memory progenitors, and they suggest a strategy for enhancing cancer immunotherapy.
Publication Title
Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 18 Downloadable Samples
- Illumina HiSeq 2000, Illumina HiSeq 2500
Description
Cancer cells must evade immune responses at distant sites to establish metastases. The lung is a frequent site for metastasis. We hypothesized that lung-specific immunoregulatory mechanisms create an immunologically permissive environment for tumor colonization. We found that T cell-intrinsic expression of the oxygen-sensing prolyl-hydroxylase (PHD) proteins is required to maintain local tolerance against innocuous antigens in the lung, but powerfully licenses colonization by circulating tumor cells. PHD proteins limit pulmonary type helper (Th)-1 responses, promote CD4+-regulatory T (Treg) cell induction, and restrain CD8+ T cell effector function. Tumor colonization is accompanied by PHD protein-dependent induction of pulmonary Treg cells and suppression of IFN-g-dependent tumor clearance. T cell-intrinsic deletion or pharmacological inhibition of PHD proteins limits tumor colonization of the lung and improves the efficacy of adoptive cell transfer immunotherapy. Collectively, PHD proteins function in T cells to coordinate distinct immunoregulatory programs within the lung that are permissive to cancer metastasis. Overall design: RNA expression was measured by RNA-Seq at day 4 following stimulation of naïve FACS-sorted CD4+ T cells with anti-CD3 and anti-CD28 antibodies in the presence of indicated doses of TGF-b. Gene expression was analysed separately in control Cd4Cre (WT) and Egln1fl/fl Egln2fl/fl Egln3fl/fl Cd4Cre (tKO) cells, or in cells treated with the pharmacological PHD inhibitor dimethyloxaloylglycine (DMOG) and control vehicle-treated cells.
Publication Title
Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
To better elucidate epigenetic mechanisms that correlate with the dynamic gene expression program observed after T cell activation, we investigated the genomic landscape of histone modifications in antigen-experienced CD8+ T cells. Using a ChIP-Seq approach coupled with global gene expression profiling, we generated genome-wide histone H3 lysine 4 (H3K4me3) and H3 lysine 27 (H3K27me3) trimethylation maps in distinct subsets of CD8+ T cells-nave, stem cell memory, central memory, and effector memory-to gain insight into how histone architecture is remodeled during the differentiation of activated T cells. We show that H3K4me3 histone modifications are associated with activation of genes, while H3K27me3 is negatively correlated with gene expression at canonical loci and enhancers regions associated with T cell metabolism, effector function, and memory. Our results also reveal histone modifications and gene expression signatures that distinguish the recently identified stem cell memory T cell from other antigen-experienced CD8+ T cell subsets. Taken together, our results suggest that antigen-experienced T cells may undergo chromatin remodeling in a progressive fashion that may have implications for our understanding of peripheral T cell ontogeny and the formation of immunological memory.
Publication Title
Lineage relationship of CD8(+) T cell subsets is revealed by progressive changes in the epigenetic landscape.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in EMT-dependent tumor metastasis. While the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is upregulated by activated T cells, specifically in the KLRG1hi effector CD8+ T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8+ T cells following primary and secondary infection with a severe impairment in the generation of the KLRG1hi effector-memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress CD127 and IL-2 in CD8+ T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box-sites in the ZEB2 gene and that T-bet and ZEB2 regulate similar gene-expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Taken together, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8+ T cells.
Publication Title
Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 33 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Adoptive immunotherapies using genetically-redirected T cells expressing a chimeric antigen receptor (CAR) or T cell receptor (TCR) are poised to enter mainstream clinical practice. Despite encouraging results, some patients fail to respond to current therapies. In part, this phenomenon has been associated with infusion of a reduced number of early memory T cells. Herein, we report that pharmacologic disruption of AKT-signaling (AKTi) is compatible with the transduction of both CARs and TCRs into human T cells and promotes a minimally differentiated CD62L-expressing phenotype. Critically, this intervention did not compromise cell yield. Mechanistically, disruption of AKT-signaling preserved MAPK activation and promoted the intra-nuclear accumulation of FOXO1, a key transcriptional regulator of T-cell memory. Consequently, AKTi synchronized the T-cell transcriptional profile for FOXO1-dependent target genes across multiple donors. Expression of an AKT-resistant FOXO1 mutant phenocopied the influence of AKTi while addition of AKTi to T cells expressing mutant FOXO1 failed to further augment the frequency of CD62L-expressing cells. Finally, CD19 CAR-modified T cells transduced and expanded in AKTi treated established B-cell acute lymphoblastic leukemia superiorly to conventionally grown T cells in a murine xenograft model. Thus, inhibition of AKT-signaling represents a generalizable strategy to generate large numbers of receptor-modified T cells with an early memory phenotype.
Publication Title
Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy.
Sample Metadata Fields
Treatment, Subject, Time
View Samples- Mus musculus
- 28 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Serial comparison between Th1 and Th17 tumor-specific cells cultured in vitro and ex vivo after transferred into sublethaly irradiated B6.PL mice. Th17-derived cells acquire Th1-like properties in vivo but maintain a distinct molecular profile.
Publication Title
Th17 cells are long lived and retain a stem cell-like molecular signature.
Sample Metadata Fields
Specimen part, Treatment
View Samples