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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).

ORGANISM(S): Homo sapiens

PROVIDER: GSE41909 | GEO | 2012/11/16

SECONDARY ACCESSION(S): PRJNA178466

REPOSITORIES: GEO

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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). 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.

2012-11-16 | E-GEOD-41909 | biostudies-arrayexpress

Effect of anti-IL-15 administration on T cell and NK cell homeostasis in rhesus macaques (TCM)

Project description:Analysis of the effect of anti-IL-15 monoclonal antibody treatment on T cell and NK cell homeostasis in rhesus macaques. The hypothesis tested in the present study was that repeated administrations of a rhesusized anti-IL-15 monoclonal antibody would block IL-15 activity in vivo and result in changes to T and/or NK cell population dynamics that would reflect physiologic IL-15 function. The results provide important information on the specific role IL-15 plays in effector memory T cell and NK cell homeostasis, noting that effector memory T cells but not NK cells can be maintained in the absence of IL-15 signaling by the activity of other cytokines. Sort-purified CD8+ and CD4+ TCM from PBMC, before and after treatment with IgG1 Ab and anti-IL15 Ab

2016-09-07 | E-GEOD-76785 | biostudies-arrayexpress

Targeting IL-21 to tumor-reactive T cells enhances memory T cell responses and anti-PD-1 antibody therapy

Project description:T cell rejuvenation by PD-1/PD-L1 blockade, despite emerging as a highly promising therapy for advanced cancers, is only beneficial for a minority of treated patients. There is evidence that a lack of efficient T cell activation may be responsible for the failure. Here, we demonstrate that IL-21 can be targeted to tumor-reactive T cells by fusion of IL-21 to anti-PD-1 antibody. To our surprise, the fusion protein PD-1Ab21 promoted the generation of TSCM-like CD8+ T cells with enhanced cell proliferation. A transcriptome analysis of isolated TN, activated and PD-1Ab-cultured CD44highCD62Lhigh T cells, IL-2-generated TE/TEM, IL-15-generated TCM as well as PD-1Ab21 and IL-21-generated CD44lowCD62Lhigh T cells provides corroborating evidence that PD-1Ab21 induces conversion of activated CD8+ T cells back to a memory subset that is distinct from TCM cells, but similar to TSCM. PD-1Ab21 treatment showed potent antitumor effects in established tumor-bearing mice accompanied with an increased frequency of TSCM and robust expansion of tumor-specific CD8+ T cells with a memory phenotype, and was superior to a combination of PD-1 blockade and IL-21 infusion. Therefore, we have developed a potential strategy to improve the therapeutic effects of immune checkpoint blockade by simultaneously targeting cytokines to tumor-reactive T cells.

2021-01-01 | GSE164093 | GEO

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

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

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.

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

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

Transcriptome of CD8+T-cells from C57BL/6 mice in induced tumor-like conditions along with IL-2 and IL-12.

Project description:To study differentially expressed genes via RNA seq analysis of CD8+T-cells from C57BL/6 mice splenocytes treated with the four different conditions: IL-2, IL-2 80%TCM, IL-12 and IL-12 80%TCM. (TCM = Tumor Conditioned Media)

2021-11-23 | GSE189170 | GEO

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