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IL-7 and IL-15 instruct the generation of human memory stem T cells from naïve precursors

ABSTRACT: The identification of the most appropriate T-cell subset to ensure optimal persistence and anti-tumor activity is a major goal of cancer immunotherapy. We identified a novel post-mitotic CD45RA+CD62L+ T cell subpopulation (TTN), generated in vitro upon activation of naïve T (TN) cells with beads conjugated to anti-CD3 and anti-CD28 antibodies. This cell population is highly proliferative, produces low levels of IFNg and cytotoxic molecules, and requires IL-7 and IL-15 for in vitro expansion. To investigate whether this cell population represents a novel T-cell subset, we compared the transcriptomic profile of TTN with that of other T-cell subsets, namely naturally occurring TN and central memory (TCM) and manipulated cells of TCM origin (TTCM). We collected RNA from unmanipulated purified T-cell subsets (TN and TCM) or from T-cell subsets that were in vitro activated and transduced (TTN and TTCM). In vitro generated subsets were kept in culture for 15 days after activation before harvesting. Samples were then processed for total RNA extraction and hybridization on Affymetrix microarrays. Three biological replicas (A, B, C) were used for each of the 4 conditions (1: TN; 2: TCM; 3: TTN; 4: TTCM) for a total of 12 samples.

ORGANISM(S): Homo sapiens

SUBMITTER: Silvio Bicciato

PROVIDER: E-GEOD-41909 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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IL-7 and IL-15 instruct the generation of human memory stem T cells from naïve precursors

Project description:The identification of the most appropriate T-cell subset to ensure optimal persistence and anti-tumor activity is a major goal of cancer immunotherapy. We identified a novel post-mitotic CD45RA+CD62L+ T cell subpopulation (TTN), generated in vitro upon activation of naïve T (TN) cells with beads conjugated to anti-CD3 and anti-CD28 antibodies. This cell population is highly proliferative, produces low levels of IFNg and cytotoxic molecules, and requires IL-7 and IL-15 for in vitro expansion. To investigate whether this cell population represents a novel T-cell subset, we compared the transcriptomic profile of TTN with that of other T-cell subsets, namely naturally occurring TN and central memory (TCM) and manipulated cells of TCM origin (TTCM).

2012-11-16 | GSE41909 | GEO

Transcription profiling of human CD8 naive (TN), central memory (TCM), effector memory (TEM), and effector memory RA (TEMRA) T cells

Project description:Memory T cells are heterogeneous in terms of their phenotype and functional properties. We investigated the molecular profiles of human CD8 naïve (TN), central memory (TCM), effector memory (TEM), and effector memory RA (TEMRA) T cells using gene expression microarrays and phospho-protein-specific intracellular flow cytometry. We demonstrate that TCM have a gene expression and cytokine signaling signature that lies between that of TN and TEM or TEMRA cells, whereas TEM and TEMRA are closely related. Our data define the molecular basis for the different functional properties of central and effector memory subsets. We show that TEM and TEMRA cells strongly express genes with known importance in CD8 T cell effector function. In contrast, TCM are characterized by high basal and cytokine-induced STAT5 phosphorylation, reflecting their capacity for self-renewal. Altogether, our results distinguish TCM and TEM/TEMRA at the molecular level and are consistent with the concept that TCM represent memory stem cells.

2005-01-01 | E-TABM-40 | biostudies-arrayexpress

Gene expressions of CD4+ T cells in each developmental stages

Project description:The development of T cells has been characterized as taking place over three stages: naïve (Tn), central memory (Tcm), and effector memory (Tem) cells. Recently, stem cell memory T cells (Tscm) were found to be the least-developed memory subset. We performed detailed analysis of the gene expression of human CD4+ T cells with clear distinction of the Tn, Tscm, Tcm, and Tem stages. We sorted Tn, Tscm, Tcm, and Tem CD4+ T cells from the peripheral blood of six healthy volunteers to see the differences of gene expression between each developmental stage.

2015-05-12 | E-GEOD-61697 | biostudies-arrayexpress

Expression data from human naïve (TN), stem cell memory (TSCM), central memory (TCM) and effector memory (TEM) CD8+ T cells

2011-07-13 | GSE23321 | GEO

Gene expressions of CD4+ T cells in each developmental stages

2015-05-12 | GSE61697 | GEO

Gene expressions of CD4+ T cells from patients with rheumatoid arthritis in each developmental stages

Project description:The development of T cells has been characterized as taking place over three stages: naïve (Tn), central memory (Tcm), and effector memory (Tem) cells. Recently, stem cell memory T cells (Tscm) were found to be the least-developed memory subset. We performed detailed analysis of the gene expression of human CD4+ T cells from patients with rheumatoid arthritis with clear distinction of the Tn, Tscm, Tcm, and Tem stages.

2021-04-01 | GSE80785 | GEO

Activated-memory T cells influence naïve T cell fate: A non-cytotoxic function of human CD8 T cells

Project description:T cells are endowed with the capacity to sense their environment including other T cells 48 around them. They do so to set their numbers and activation thresholds. This form of regulation has been well-studied within a given T cell population – i.e., within the naïve or memory pool; however, less is known about the cross-talk between T cell subsets. Here, we tested whether memory T cells interact with and influence surrounding naïve T cells. We report that human naïve CD8 T cells (TN) undergo phenotypic and transcriptional changes in the presence of autologous activated-memory CD8 T cells (TMem). Following in vitro co-culture with activated central memory cells (TCM), ~3% of the TN acquired activation/memory canonical markers (CD45RO and CD95) in an MHC-I dependent-fashion. Using scRNA-seq, we also observed that ~3% of the TN acquired an activated/memory signature, while ~84% developed a unique activated transcriptional profile hybrid between naïve and activated memory. Pseudotime trajectory analysis provided further evidence that TN with an activated/memory or hybrid phenotype were derived from TN. Our data reveal a non-cytotoxic function of TMem with potential to activate autologous TN into the activated/memory pool. These findings may have implications for host-protection and autoimmunity that arises after vaccination, infection or transplantation

2022-06-29 | GSE202548 | GEO

Long-term expansion using IL-7 and IL-15 increases T cell yield with preserved Tcm/Tscm properties suitable for adoptive T cell therapy

Project description:Adoptive T cell therapy (ATT) requires activation, expansion and, for certain indications, gene-modification of T cells. Sufficient numbers of T cells and the characteristics of the final T cell product decisively determine the success of treatment. In this study, we addressed the question if prolonged expansion by simply using the cytokine combination IL-7/IL-15 could enhance the T cell yield without sacrifying T cell functionality. Prolonged expansion resulted in a 50-fold increase of CD8+ central memory T cells (Tcm). RNA sequencing and differential analysis of short-term expanded (ST) and long-term expanded (LT) murine CD8+ and CD4+ Tcm revealed that LT T cells retain a gene expression profile related to Tcm/stem central memory T cells (Tscm). Upon anti-CD3/CD28 stimulation, ST and LT T cells proliferated and underwent apoptosis comparably. IL-2 and INF- production was higher for LT T cells. Engraftment, persistence and anti-tumor capacities of LT murine T cells were preserved after in vivo administration. We confirmed our in vitro findings for human T cells. Our study demonstrates the feasibility of manufacturing an increased number of favorable T cells with Tcm/Tscm properties for ATT by a prolonged, minimally manipulative expansion protocol using the cytokines IL-7 and IL-15.

2021-01-28 | GSE140250 | GEO

Expression data from human naïve (TN), stem cell memory (TSCM), central memory (TCM) and effector memory (TEM) CD8+ T cells

Project description:An early-differentiated CD8+ memory T cell subset with stem cell-like properties (TSCM) can be identified within the naïve-like T cell population by the expression of CD95/Fas. Based on experiments including exon- and gene-level expression analysis, we provide evidence that this subset of antigen-specific cells represents an early precursor of conventional central (TCM) and effector (TEM) memory CD8+ T cells with enhanced self-renewal capacity and proliferative potential. We identified 900 genes differentially expressed between major T cell subsets defined along with memory T cell commitment. Based on the analysis of these genes, CD95+ naïve T cells (TSCM) cluster closer to the CD8+ T memory compartment than to classical (CD95-) naïve T (TN) cells, and display an intermittent phenotype between classical TN and TCM cells in terms of all major T cell differentiation markers analyzed. Three healthy human blood donors provided lymphocyte-enriched apheresis blood for this study after informed consent. From all samples, total RNA was isolated using an RNEasy Micro kit (Qiagen), processed by Ambion’s WT expression kit, fragmented and labeled with a WT Terminal Labeling Kit (Affymetrix), hybridized to WT Human Gene 1.0 ST arrays (Affymetrix) and stained on a Genechip Fluidics Station 450 (Affymetrix), all according to the respective manufacturer's instructions. Samples represent "exon-level" and "gene-level" analyses.

2011-07-12 | E-GEOD-23321 | biostudies-arrayexpress

Gene expression differences between low IL2/7- and high IL-2-expanded CD8+ T effectors at day 8 of LCMV Armtrong infection

Project description:Here, we reported a novel subset of CD8+ T effectors with transcriptional similarity to central memory CD8+ T cells (Tcm). Such CD8+ T effectors were characterized with abundant surface expression of both Cxcr3 and CD62L and possessed strong stemness. These CD8+ T effectors mainly developed into Tcm in adoptive transfer and exclusively possessed the capacity to generate Tcm in antigen re-stimulation, indicating they functioned to be Tcm precursors. These Cxcr3+CD62L+ Tcm precursors were determined by high expression of T cell transcription factor 1 (TCF-1), which guaranteed CD62L expression by binding to distal enhancers of Sell (gene symbol for CD62L). Cxcr3+CD62L+ Tcm precursors could be massively obtained by expansion of anti-CD3/28 activated CD8+ T cells with low IL-2 plus IL-7, and these in vitro-expanded Cxcr3+CD62L+ Tcm precursors exhibited strong effective in tumor elimination and were better than conventional high IL-2 expanded-CD8+ T effectors for clearance of tumors.

2022-09-07 | GSE212687 | GEO

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