Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Effect of rBTNL2.Fc co-stimulation on murine CD4+ cells

ABSTRACT: Naïve T cell activation involves at least two signals from an antigen presenting cell (APC), one through the T cell receptor via interaction with APC peptide-MHC complexes and a second through interaction of CD28 with APC B7 ligands. Following activation, T cells up-regulate a host of other membrane-bound costimulatory molecules which can either promote or inhibit further T cell maturation and proliferation. In some cases, it is necessary to attenuate T cell activation to prevent deleterious inflammation, and inhibitory members of the B7/Butyrophilin family of ligands have evolved to balance the strong stimuli the activating B7 ligands confer. Human genetic association and in vitro studies have implicated one such ligand, BTNL2, in controlling inflammation at mucosal surfaces. Here we show that recombinant mouse BTNL2 modifies B7/CD28 signaling to promote expression of Foxp3, a transcription factor necessary for murine Treg development and function. BTNL2 blocks Akt-mediated inactivation of Foxo1, a transcription factor necessary for Foxp3 expression. Immunophenotyping and gene profiling reveal that BTNL2-induced Treg share many properties with natural Treg, and in vivo they suppress enteritis induced by mouse effector T cells. These findings describe a mechanism by which environmental antigen-driven formation of Treg may be orchestrated by APC expressing specific modulators of costimulatory signals. CD4+CD25- cells isolated from spleen were stimulated on plates coated with anti-mouse CD3 and human IgG (negative control), anti-mouse CD3, rB7-2, and IgG (positive control), and anti-mouse CD3, rB7-2, and rBTNL2 (experimental). Culturing was performed in duplicate for each condition.

ORGANISM(S): Mus musculus

SUBMITTER: Jeannette Bigler

PROVIDER: E-GEOD-42385 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Butyrophilin-like 2 modulates B7 costimulation to induce Foxp3 expression and regulatory T cell development in mature T cells.

Swanson Ryan M RM Gavin Marc A MA Escobar Sabine S SS Rottman James B JB Lipsky Brian P BP Dube Shishir S Li Li L Bigler Jeannette J Wolfson Martin M Arnett Heather A HA Viney Joanne L JL

Journal of immunology (Baltimore, Md. : 1950) 20130128 5

Naive T cell activation involves at least two signals from an APC, one through the TCR via interaction with peptide-MHC complexes and a second through ligation of CD28 with B7 ligands. Following activation, T cells upregulate a host of other membrane-bound costimulatory molecules that can either promote or inhibit further T cell maturation and proliferation. In some cases, it is necessary to attenuate T cell activation to prevent deleterious inflammation, and inhibitory members of the B7/butyrop ...[more]

PMID: 23359506

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Project description:Regulatory T (Treg) cells are involved in self tolerance, immune homeostasis, prevention of autoimmunity, and suppression of immunity to pathogens or tumours. The forkhead transcription factor FOXP3 is essential for Treg cell development and function as mutations in FOXP3 cause severe autoimmunity in mice and humans. However, the FOXP3-dependent molecular mechanisms leading to this severe phenotype are not well understood. Here we introduce the chromatin remodelling enzyme SATB1 (special AT-rich sequence-binding protein-1) as an important target gene of FOXP3. So far, SATB1 has been associated with normal thymic T-cell development, peripheral T-cell homeostasis, TH1/TH2 polarization, and reprogramming of gene expression. In natural and induced murine and human FOXP3+ Treg cells SATB1 expression is significantly reduced. While there is no differential epigenetic regulation of the SATB1 locus between Treg and Teffector cells, FOXP3 reduces SATB1 expression directly as a transcriptional repressor at the SATB1 locus and indirectly via miR-155 induction, which specifically binds to the 3’UTR of the SATB1 mRNA. Reduced SATB1 expression in FOXP3+ cells achieved either by overexpression or induction of FOXP3 is linked to significant reduction in TH1 and TH2 cytokines, while loss of FOXP3 function either by knock down or genetic mutation leads to significant upregulation of SATB1 and subsequent cytokine production. Alltogether, these findings demonstrate that reduced SATB1 expression in Treg cells is necessary for maintenance of a Treg-cell phenotype in vitro and in vivo and places SATB1-mediated T cell-specific modulation of global chromatin remodelling central during the decision process between effector and regulatory T-cell function. Gene expression profiling of freshly isolated CD4+ T cells, separated into CD25 negative and positive subpopulations, from three different donors. FOXP3 is stably and constitutively expressed at a high level in CD4+CD25+ regulatory T cells and at a low level in CD4+CD25- cells.

Dataset Information

Effect of rBTNL2.Fc co-stimulation on murine CD4+ cells

Publications

Butyrophilin-like 2 modulates B7 costimulation to induce Foxp3 expression and regulatory T cell development in mature T cells.

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