Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Beta-tubulin and Actin Filament-Associating Small GTPase GIMAP4 is Required for IFN-Ɣ Secretion During Early Human CD4+ T Cell Activation

ABSTRACT: The aim of the dataset was to study on a genome-wide level the effect of GTPase of the human immune associated protein 4 (GIMAP4) knockdown on the gene expression of resting T cells and immediately after T cell activation and Th1(Act+IL12) polarizing conditions of human cord blood-derived CD4+ T cells. Total RNA from GIMAP4 siRNA-treated cord blood CD4+ T cells 48 hours after siRNA treatment, before TCR activation and corresponding cells cultured for 2h in TCR activating (antiCD3+antiCD28) plus IL-12 conditions was compared to total RNA from nonspecific control siRNA-treated cells. Samples from 3 biological replicates were analysed.

ORGANISM(S): Homo sapiens

SUBMITTER: Kartiek Kanduri

PROVIDER: E-GEOD-45720 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Tubulin- and actin-associating GIMAP4 is required for IFN-γ secretion during Th cell differentiation.

Heinonen Mirkka T MT Kanduri Kartiek K Lähdesmäki Harri J HJ Lahesmaa Riitta R Henttinen Tiina A TA

Immunology and cell biology 20141007 2

Although GTPase of the immunity-associated protein (GIMAP) family are known to be most highly expressed in the cells of the immune system, their function and role remain still poorly characterized. Small GTPases in general are known to be involved in many cellular processes in a cell type-specific manner and to contribute to specific differentiation processes. Among GIMAP family, GIMAP4 is the only member reported to have true GTPase activity, and its transcription is found to be differentially ...[more]

PMID: 25287446

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Project description:The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T cell fate decisions1. Activation of mTOR, comprised of mTORC1 and mTORC2 complexes, delivers an obligatory signal for proper activation and differentiation of effector CD4+ T cells2,3, whereas in the regulatory T cell (Treg) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of Treg de novo differentiation4-8 and population expansion9. However, whether mTOR signaling affects the homeostasis and function of Tregs remains largely unexplored. Here we show that mTORC1 signaling is a pivotal positive determinant of Treg function. Tregs have elevated steady-state mTORC1 activity compared to naïve T cells. Signals via T cell receptor (TCR) and IL-2 provide major inputs for mTORC1 activation, which in turn programs suppressive function of Tregs. Disruption of mTORC1 through Treg-specific deletion of the essential component Raptor leads to a profound loss of Treg suppressive activity in vivo and development of a fatal early-onset inflammatory disorder. Mechanistically, Raptor/mTORC1 signaling in Tregs promotes cholesterol/lipid metabolism, with the mevalonate pathway particularly important for coordinating Treg proliferation and upregulation of suppressive molecules CTLA-4 and ICOS to establish Treg functional competency. In contrast, mTORC1 does not directly impact the expression of Foxp3 or anti- and pro-inflammatory cytokines in Tregs, suggesting a non-conventional mechanism for Treg functional regulation. Lastly, we provide evidence that mTORC1 maintains Treg function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in Tregs to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of Treg suppressive activity in immune homeostasis and tolerance. We used microarrays to explore the gene expression profiles differentially expressed in regulatory T-cells from wild-type and CD4(cre) x Raptor(fl/fl) mice

Dataset Information

Beta-tubulin and Actin Filament-Associating Small GTPase GIMAP4 is Required for IFN-Ɣ Secretion During Early Human CD4+ T Cell Activation

Publications

Tubulin- and actin-associating GIMAP4 is required for IFN-γ secretion during Th cell differentiation.

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