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Peripheral tissue instruction is the primary determinant of CD8+ T cell pathogenicity: transcription profiling by RNA-seq of CD8+ effector T cells isolated from the blood and skin of HSCT patients developing acute pattern GVHD.

ABSTRACT: Peripheral tissue instruction is the primary determinant of CD8+ T cell pathogenicity: transcription profiling by RNA-seq of CD8+ effector T cells isolated from the blood and skin of HSCT patients developing acute pattern GVHD.

PROVIDER: PRJEB18953 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR1794850.fastq.gz	Fastqsanger.gz
	ERR1794850_1.fastq.gz	Fastqsanger.gz
	ERR1794850_2.fastq.gz	Fastqsanger.gz
	ERR1794841.fastq.gz	Fastqsanger.gz
	ERR1794841_1.fastq.gz	Fastqsanger.gz

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Peripheral tissue instruction is the primary determinant of CD8+ T cell pathogenicity: transcription profiling by RNA-seq of CD8+ effector T cells isolated from the blood and skin of HSCT patients developing acute pattern GVHD.

Project description:To determine whether murine GVHD associated tissue-specific signatures of donor CD8+ effector T cells are conserved at the same locations in humans developing GVHD, we compared the transcriptional profile of CD8+ T cells obtained simultaneously from the blood and skin of 5 patients developing acute pattern skin GVHD.

2018-03-28 | E-MTAB-5381 | biostudies-arrayexpress

Targeting Interleukin-2-Inducible T-cell Kinase (ITK) differentiates GVL and GVHD in allo-HSCT

Project description:Allogeneic hematopoietic stem cell transplantation is a potentially curative procedure for many malignant diseases. Donor T cells prevent disease recurrence via graft-versus-leukemia (GVL) effect. Donor T cells also contribute to graft-versus-host disease (GVHD), a debilitating and potentially fatal complication. Novel treatment strategies are needed which allow preservation of GVL effects without causing GVHD. Using murine models, we show that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving GVL effects. Both CD8+ and CD4+ donor T cells from Itk-/- mice produce less inflammatory cytokines and show decrease migration to GVHD target organs such as the liver and small intestine, while maintaining GVL efficacy against primary B-cell acute lymphoblastic leukemia (B-ALL). Itk-/- T cells exhibit reduced expression of IRF4 and decreased JAK/STAT signaling activity, but upregulating expression of Eomesodermin (Eomes) and preserve cytotoxicity, necessary for GVL effect. Transcriptome analysis indicates that ITK signaling controls chemokine receptor expression during alloactivation, which in turn affects the ability of donor T cells to migrate to GVHD target organs. Our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

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Peripheral tissue instruction is the primary determinant of CD8+ T cell pathogenicity: transcription profiling by array of donor CD8+ effector T cells isolated from the secondary lymphoid organs, blood and GVHD-target organs at D+6 post-transplant (B6>129 model)

Project description:This study reports the evolution of the donor CD8 effector T cell transcriptomes at multiple sites and time points within the same host following allo-SCT. Donor derived CD8+ T cells were flow sorted from multiple organs in mice developing GVHD in two clinically relevant murine models of H-2b MHC-matched minor antigen-mismatched BMT: (1) B6>129 model – transfer of C57BL/6 polyclonal CD4+ and CD8+ T cells into 129/Sv BMT recipients; (2) F>M – transfer of monoclonal HY-specific TCR-transgenic MataHari CD8+ T cells into C57BL/6 male BMT recipients.

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GVHD-mediated Vicious Cascade: Impaired Reconstitution of Immunosuppressive Donor Plasmacytoid Dendritic Cells

Project description:In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), severe graft-versus-host disease (GVHD) is tied to failed donor plasmacytoid DC (pDC) reconstitution. The mechanism whereby GVHD causes donor pDC defects and the precise role donor pDCs play in GVHD remain poorly understood. pDCs develop from HSCs in successive stages through Flt3 signaling-dependent differentiation, beginning as multi-potent progenitors (MPPs) and later becoming common DC progenitors. We observed that MPPs were critical for sustaining pDCs and were severely depleted during GVHD. Loss of MPPs was associated with decreased amounts of MPP-producing HSCs and mTOR activation-induced cell death of proliferating MPPs. Additionally, GM-CSF derived from alloreactive T cells subverted MPP production of pDCs. Together, GVHD and alloreactive T cells caused donor pDC defects by impairing the generation, maintenance and differentiation of HSCs and MPPs. Importantly, pDCs suppressed the proliferation and expansion of activated autologous CD4+ T cells via a type I-IFN signaling-dependent mechanism. Transfer of donor pDCs early after transplantation repressed GVHD and preserved potent GVL effects, significantly improving the survival of leukemia mice undergoing allo-HSCT. Our findings identify novel strategies that improve the recovery of donor pDCs early after allo-HSCT and thus may represent an effective therapy to control GVHD. Our findings have broad implications for other diseases in which functional DC development is impaired, such as chronic infections, autoimmunity and cancer.

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Project description:IL-17-producing cells are important mediators of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Here we demonstrate that a distinct CD8+ Tc17 population develops rapidly after SCT but fails to maintain lineage fidelity such that they are unrecognizable in the absence of a fate reporter. Tc17 differentiation is dependent on alloantigen presentation by host-DC together with IL-6. Tc17 cells express high levels of multiple prototypic lineage-defining transcription factors (e.g. RORgt, T-bet) and cytokines (e.g. IL-17A, IL-22, IFNg, GM-CSF, IL-13). Targeted depletion of Tc17 early after transplant protects from lethal acute GVHD, however Tc17 cells are non-cytolytic and fail to mediate graft–versus–leukemia (GVL) effects. Thus, the Tc17 differentiation program during GVHD culminates in a highly plastic, hyper-inflammatory, poorly-cytolytic effector population which we term inflammatory Tc17 (iTc17). Since iTc17 mediate GVHD without contributing to GVL, therapeutic inhibition of iTc17 development in a clinical setting represents an attractive approach for separating GVHD and GVL. Single colour, Illumina MouseRef-8 v2.0 Beadarrays.

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Transcriptional analysis of beta-catenin overexpressing T cells

Project description:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most widely applied forms of adaptive immunotherapy. Both the detrimental graft-versus-host disease (GVHD) and the beneficial graft-versus-leukemia (GVL) effects occurring after allo-HSCT are largely mediated by alloantigen-reactive donor T cells in the graft. Separating GVHD from GVL effects is a formidable challenge, and a greater understanding of donor T cell biology is required to accomplish the uncoupling of GVHD from GVL. Here, we tested a novel mouse model of transgenic over-expression of human β-catenin (Cat-Tg) in an allo-HSCT model. Our data show that T cells from Cat-Tg mice did not cause GVHD. Surprisingly, Cat-Tg T cells maintained the GVL effect. Donor T cells from Cat-Tg mice exhibited significantly lower inflammatory cytokine production and reduced donor T cell proliferation, while upregulating cytotoxic mediators that resulted in enhanced cytotoxicity. RNA sequencing data revealed changes in the expression of 1169 genes for CD4, and 1006 genes for CD8+T cells involved in essential aspects of immune response and GVHD pathophysiology. Transgenic over-expression of human β-catenin primarily affects CD8+ T cell phenotype. Altogether, our data suggest that β-catenin is a druggable target for developing therapeutic strategies to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment

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Project description:In comparison with allogeneic hematopoietic stem cell transplantation using other sources, umbilical cord blood transplantation (UCBT) offers substantial clinical advantages including a lower incidence and severity of acute graft-versus-host disease (GVHD) despite the use of allogeneic UCB stem cells with more disparate HLA. However, detailed pathophysiology of acute GVHD developed after UCBT has not yet been clarified. Here, we examined the roles of inflammatory cells in the pathogenesis of acute GVHD following UCBT, by expression profiling of a total of 595 genes in each of 4 subsets (CD4+, CD8+, CD14+, and CD56+) of peripheral blood mononuclear cells (PBMCs), which were taken from 3 patients with hematologic malignancy, in whom acute GVHD had developed after UCBT. We compared expression profiles measured during acute GVHD with those measured opon discharge (recovery phase), for each subset of PBMCs to identify immuno-regulatory genes which were assumed to be linked to the pathogenesis of acute GVHD. Keywords: disease state analysis Peripheral blood mononuclear cells (PBMCs) were taken from 3 patients with hematologic malignancy, in whom acute GVHD had developed after cord blood transplantation. CD4+, CD8+, CD14+, and CD56+ cell subsets were isolated from the PBMCs of 2 patients, while only CD8+ and CD56+ cell subsets were isolated from the PBMCs of a patient. PBMCs were taken twice - during acute GVHD phase and upon discharge (recovery phase), from each patient. By using a custom-made fibrous oligonucleotide DNA microarray Genopal (Mitsubishi Rayon), we compared expression profiles of 595 unique genes measured during acute GVHD with those measured upon discharge (recovery phase), for each subset of PBMCs.

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