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Integrin alpha-6 (CD49f) defines a novel and distinct subset of CD4+ regulatory T cells with potent suppression activity.

ABSTRACT: A common method used both in vitro and in vivo, to identify Tregs in CD4+ T cells is through the characterization of surface marker CD25. Although CD25 expression is well correlated with regulatory activity in vitro, CD4+CD25+ T cells are not the only regulatory CD4+ T cells in vivo. Studies suggest that in many situations, CD4+CD25– T cells are as effective as CD4+CD25+ T cells in controlling T cell mediated disease. Therefore, CD25 is not a uniquely specific cell surface marker for the identification of Tregs. CD49f is an α6-integrin subunit which dimerizes with either the β 1 or β 4 subunit to form receptors for various laminin isoforms. We found that CD4+ T cells from NOD mice express CD49f, and old non-diabetic NOD mice had an increase of CD4+CD49f+ T cells in the spleen and peripheral lymph node when compared to both young and diabetic mice. This study was conducted to further characterize CD4+CD49f+ Treg cell subpopulation in NOD mice. It was found that CD4+CD49f+T cells possess suppressive ability and only one third of CD4+CD49f+ T cells expressing CD25. Based on the expression of CD49f and CD25, CD4+ T cells was divided into four populations , CD25+CD49f+ ,CD25+CD49f- ,CD25-CD49f+ but CD25-CD49f- are of suppressive ability, and we further found that Foxp3 expression was highly correlated with the suppressive ability of these three Treg populations. In conclusion our data indicate that CD49f marks a CD4+ CD25+ Treg subset with more potent suppression activity and identifies a CD25-CD4+ T cell population with suppression function in a Foxp3+ expression dependent manner.

ORGANISM(S): Mus musculus

PROVIDER: GSE30503 | GEO | 2012/05/10

SECONDARY ACCESSION(S): PRJNA143315

REPOSITORIES: GEO

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Integrin alpha-6 (CD49f) defines a novel and distinct subset of CD4+ regulatory T cells with potent suppression activity.

Project description:A common method used both in vitro and in vivo, to identify Tregs in CD4+ T cells is through the characterization of surface marker CD25. Although CD25 expression is well correlated with regulatory activity in vitro, CD4+CD25+ T cells are not the only regulatory CD4+ T cells in vivo. Studies suggest that in many situations, CD4+CD25M-bM-^@M-^S T cells are as effective as CD4+CD25+ T cells in controlling T cell mediated disease. Therefore, CD25 is not a uniquely specific cell surface marker for the identification of Tregs. CD49f is an M-NM-16-integrin subunit which dimerizes with either the M-NM-2 1 or M-NM-2 4 subunit to form receptors for various laminin isoforms. We found that CD4+ T cells from NOD mice express CD49f, and old non-diabetic NOD mice had an increase of CD4+CD49f+ T cells in the spleen and peripheral lymph node when compared to both young and diabetic mice. This study was conducted to further characterize CD4+CD49f+ Treg cell subpopulation in NOD mice. It was found that CD4+CD49f+T cells possess suppressive ability and only one third of CD4+CD49f+ T cells expressing CD25. Based on the expression of CD49f and CD25, CD4+ T cells was divided into four populations , CD25+CD49f+ ,CD25+CD49f- ,CD25-CD49f+ but CD25-CD49f- are of suppressive ability, and we further found that Foxp3 expression was highly correlated with the suppressive ability of these three Treg populations. In conclusion our data indicate that CD49f marks a CD4+ CD25+ Treg subset with more potent suppression activity and identifies a CD25-CD4+ T cell population with suppression function in a Foxp3+ expression dependent manner. We divided CD4+ T cells into four populations: CD25+CD49f+, CD25+CD49f-, CD25-CD49f+, CD25-CD49f-; Microarray technology was used to determine gene expression differences among these four groups.

2012-05-09 | E-GEOD-30503 | biostudies-arrayexpress

Gene expression profiles of CD4+CD25+ Tregs from NOD and B6.H2g7 mice

Project description:The NOD (nonobese diabetic) mouse strain develops a characteristic autoimmune syndrome that closely resembles human type I diabetes. It has been suggested that NOD mice exhibit both numerical deficiency in CD4+CD25+ regulatory T cells (Treg) and reduced suppressive activity. We compared sorted CD4+CD25+ Tregs from the spleens of 6-7 week-old female NOD and nondiabetic B6.H2g7 mice. Tregs were 93±2% and 95±1% Foxp3+ in NOD and B6.H2g7 cells, respectively, on post-sort reanalysis. "Conventional" CD4+CD25- T cells (Tconv) are included as reference populations. Surprisingly, Treg "signature" is similar between the two strains, with only a few probesets that subtly deviate. Keywords: Cell population comparison from two mouse strains. For each strain (NOD and B6.g7), we analyzed two populations: CD4+CD25+ Treg and CD4+CD25- Tconv cells, for a total of four distinct populations. RNA from three mice were pooled for each replicate; there are three independent replicates for each population. After RMA normalization, intensity values were averaged across the three replicates and analyzed. We calculated the ratio of Treg/Tconv intensity values for each strain and compared the results.

2008-12-19 | E-GEOD-6813 | biostudies-arrayexpress

Gene expression profiles of CD4+CD25+ Tregs from NOD and B6.H2g7 mice

2008-12-19 | GSE6813 | GEO

CD49f defines a subset of dysfunctional regulatory T cells circulating in the human peripheral blood

Project description:The therapeutic use of regulatory T cells (Tregs) in patients with autoimmune disorders has been hampered by the biological variability of memory Treg populations in the peripheral blood. In this study, we reveal through a combination of quantitative proteomic, multiparametric flow cytometry, RNA-seq data analysis and functional assays, that CD49f is heterogeneously expressed among human Tregs and impacts their immunomodulatory function. High expression of CD49f defines a subset of dysfunctional Tregs in the human blood characterized by a Th17-like phenotype and impaired suppressive capacity. CD49f is similarly distributed between naïve and memory Tregs and impacts the expression of CD39, CTLA-4, FoxP3 and CCR6 specifically in the memory compartment. Accumulation of CD49f high memory Tregs in the blood of ulcerative colitis patients correlates with disease severity. Our results highlight important considerations for Treg immunotherapy design in patients with inflammatory bowel disease which could possibly extend to other autoimmune disorders.

2021-08-06 | PXD022095 | Pride

Mbd2 promotes Foxp3 demethylation and T-regulatory cell function

Project description:The proposed use of Foxp3+ T-regulatory (Treg) cells as potential cellular therapy in patients with autoimmune diseases, or post-hemopoietic stem cell or organ transplantation, requires a sound understanding of the transcriptional regulation of Foxp3 expression. Conserved CpG dinucleotides in the Treg-specific demethylated region (TSDR) upstream of Foxp3 are demethylated only in stable, thymic-derived Foxp3+ Tregs. Since methyl-binding domain (Mbd) proteins recruit histone-modifying and chromatin-remodeling complexes to methylated sites, we tested whether targeting of Mbd2 might promote demethylation of Foxp3 and thereby promote Treg numbers or function. Surprisingly, while ChIP analysis showed Mbd2 binding to the Foxp3-associated TSDR site in Tregs, Mbd2 targeting by homologous recombination or siRNA decreased Treg numbers and impaired Treg suppressive function in vitro and in vivo. Moreover, we found complete TSDR demethylation in WT Tregs but >75% methylation in Mbd2-/- Tregs, whereas re-introduction of Mbd2 into Mbd2-null Tregs restored TSDR demethylation, Foxp3 gene expression and Treg suppressive function. Lastly, Mbd2-/- Tregs had markedly binding of the DNA demethylase enzyme, Tet2, in the TSDR region. These data show that Mbd2 has a key role in promoting TSDR demethylation, Foxp3 expression and Treg suppressive function. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of MBD2–/– mice, compared to wild type control (all Balb/c background).

2013-09-01 | E-GEOD-48653 | biostudies-arrayexpress

Critical Requirement of the DNA Methyltransferase, Dnmt1, for the Development and Function of Foxp3+ Regulatory T Cells

Project description:We investigated the role of DNMT1 in immune homeostasis by generating mice lacking DNMT1 in Foxp3+ T-regulatory (Treg) cells. These mice showed decreased peripheral Foxp3+ Tregs, complete loss of Foxp3+ Treg suppressive functions in vitro and in vivo, and died from autoimmunity by 3-4 weeks unless they received perinatal transfer of wild-type Tregs that prolonged their survival. Methylation of CpG-sites in the TSDR region of Foxp3 was unaffected by DNMT1 deletion, but microarray revealed more >500 proinflammatory and other genes were upregulated in DNMT1-/- Tregs. CD4-Cre-mediated DNMT1 deletion showed inability of conventional T cells to convert to Foxp3+ Treg under appropriate polarizing conditions. Hence, DNMT1 is absolutely necessary for maintenance of the gene program required for normal Treg development and function. RNA from three independent samples of magnetically separated CD4+CD25+ Treg of fl-DNMT1/Foxp3cre mice, compared to wild type (C57BL6) control

2013-04-21 | E-GEOD-27434 | biostudies-arrayexpress

Microarray analysis of FoxP3-expressing or non-expressing subsets of human CD4+ T cells

Project description:Gene expression profiles of subsets of CD4+ T cells according to their expression of FoxP3 and CD45RA were compared. Abstract: FoxP3 is a key transcription factor for the development and function of natural CD4+ regulatory T cells (Tregs). Here we show that human FoxP3+CD4+ T cells are composed of three phenotypically and functionally distinct subpopulations: CD45RA+FoxP3low resting Tregs (rTregs) and CD45RA-FoxP3high activated Tregs (aTregs), both of which are suppressive in vitro, and cytokine-secreting CD45RA-FoxP3low non-suppressive T cells. The proportion of the three subpopulations characteristically altered in cord blood, aged individuals, and patients with immunological diseases. Terminally differentiated aTregs rapidly die while rTregs proliferate and convert into aTregs in vitro and in vivo as shown by the transfer of rTregs into NOD-scid-common gamma-chain-knockout mice and by TCR sequence-based T cell clonotype tracing in peripheral blood of normal individuals. Taken together, the dissection of FoxP3+ cells into subsets enables one to analyze Treg differentiation dynamics and interactions in normal and disease states, and to control immune responses through manipulating particular FoxP3+ subpopulations. RNA was extracted from freshly obtained peripheral blood lymphocytes from a healthy donor that were separated according to their expression of CD25, CD127 and CD45RA after surface staining.

2009-05-21 | E-GEOD-15659 | biostudies-arrayexpress

Gene expression profiling of CD4+CD25+Foxp3+ regulatory T cells and CD4+CD25-Foxp3- T cells in the course of Plasmodium yoelii infection of BALB/c mice

Project description:The objective of the present study was to characterize the phenotype of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in the course of parasitic Plasmodium yoelii (P .yoelii) infection of BALB/c mice. Therefore we performed microarray expression analysis of CD4+CD25+Foxp3+ Tregs isolated by FACS from spleens of non-infected mice and from spleens of mice infected with P. yoelii 3 days and 5 days post infection. By comparing the gene expression profiles, we were able to identify molecules which were differentially expressed by Tregs during parasitic infection and thereby might be involved in their immune-suppressive function. Moreover, we included CD4+CD25-Foxp3- T cells from spleens of non-infected and P. yoelii-infected mice in our analysis. It was proposed that immune-suppressive CD4+CD25-Foxp3- T cells might be induced during Plasmodium infection of mice. Thus, detailed gene expression data of these cells in comparison to CD4+CD25+Foxp3+ Tregs would contribute a better understanding in the phenotype. FACS sorted CD4+CD25+Foxp3+ Tregs and CD4+CD25-Foxp3- T cells from pooled spleens of non-infected Foxp3/ eGFP mice (served as reference) and from pooled spleens of P. yoelii infected Foxp3/ eGFP mice 3 days and 5 days post infection were analyzed as single probes.

2012-04-15 | E-GEOD-34621 | biostudies-arrayexpress

Inhibition of p300 impairs Foxp3+ T-regulatory cell function and promotes anti-tumor immunity

Project description:Foxp3+ T-regulatory (Treg) cells maintain immune homeostasis and limit autoimmunity, but can also curtail host responses to cancers. Tregs are therefore promising targets to enhance anti-tumor immunity. Histone/protein acetyltransferases (HATs) promote chromatin accessibility, gene transcription and the function of multiple transcription factors and non-histone proteins. We found that conditional deletion or pharmacologic inhibition of one specific HAT, p300, in Foxp3+ Tregs, increased TCR-induced apoptosis in Tregs, impaired Treg suppressive function and iTreg peripheral conversion, and limited tumor growth in immunocompetent, but not in immunodeficient, hosts. Our data demonstrate that p300 is important for Foxp3+ Treg function and homeostasis in vivo and in vitro, and identify a novel mechanism to diminish Treg function without overtly impairing effector Tcell responses or inducing autoimmunity. Collectively, these data suggest a new approach for cancer immunotherapy. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of fl-p300/Foxp3cre mice, compared to wild type (Foxp3cre) control (all C57Bl/6 background).

2013-08-18 | E-GEOD-47989 | biostudies-arrayexpress

Expression profiling of WT and p110delta D910A Treg

Project description:The PI3K pathway has emerged as a key regulator of regulatory T cell (Treg) development and homeostasis and is required for full Treg-mediated suppression. To identify new genes involved in PI3K-dependent suppression we compared the transcriptome of WT and p110delta D910A Tregs. Among the genes that were differentially expressed was CD38. Here we show that CD38 is expressed mainly by a subset of Foxp3+CD25+CD4+ T cells originating in the thymus and on Tregs in the spleen. CD38high WT Tregs showed superior suppressive activity and CD38low Tregs failed to upregulate CD73, a surface protein which is important for suppression. However, Tregs from heterozygous CD38+/- mice were unimpaired despite their lower levels of CD38 expression. Therefore, CD38 can be used as a marker for Tregs with high suppressive activity and the impaired Treg function in p110delta D910A mice can in part be explained by the failure of CD38high cells to develop.

2011-04-01 | E-MEXP-2955 | biostudies-arrayexpress

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