Publications by authors named "Hozefa Bandukwala"

22 Publications

  • Page 1 of 1

Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation.

Nat Immunol 2015 Dec 2;16(12):1228-34. Epub 2015 Nov 2.

Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.

The molecular mechanisms that link the sympathetic stress response and inflammation remain obscure. Here we found that the transcription factor Nr4a1 regulated the production of norepinephrine (NE) in macrophages and thereby limited experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Lack of Nr4a1 in myeloid cells led to enhanced NE production, accelerated infiltration of leukocytes into the central nervous system (CNS) and disease exacerbation in vivo. In contrast, myeloid-specific deletion of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, protected mice against EAE. Furthermore, we found that Nr4a1 repressed autocrine NE production in macrophages by recruiting the corepressor CoREST to the Th promoter. Our data reveal a new role for macrophages in neuroinflammation and identify Nr4a1 as a key regulator of catecholamine production by macrophages.
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http://dx.doi.org/10.1038/ni.3321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833087PMC
December 2015

Inhibition of FOXP3/NFAT Interaction Enhances T Cell Function after TCR Stimulation.

J Immunol 2015 Oct 31;195(7):3180-9. Epub 2015 Aug 31.

Gene Therapy and Hepatology Division, Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain;

Regulatory T cell (Treg) activity is modulated by a cooperative complex between the transcription factor NFAT and FOXP3, a lineage specification factor for Tregs. FOXP3/NFAT interaction is required to repress expression of IL-2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function to Tregs. However, FOXP3 is expressed transiently in conventional CD4(+) T cells upon TCR stimulation and may lead to T cell hyporesponsiveness. We found that a short synthetic peptide able to inhibit FOXP3/NFAT interaction impaired suppressor activity of conventional Tregs in vitro. Specific inhibition of FOXP3/NFAT interaction with this inhibitory peptide revealed that FOXP3 downregulates NFAT-driven promoter activity of CD40L and IL-17. Inhibition of FOXP3/NFAT interaction upregulated CD40L expression on effector T cells and enhanced T cell proliferation and IL-2, IFN-γ, IL-6, or IL-17 production in response to TCR stimulation. The inhibitory peptide impaired effector T cell conversion into induced Tregs in the presence of TGF-β. Moreover, in vivo peptide administration showed antitumor efficacy in mice bearing Hepa129 or TC1 tumor cells when combined with sorafenib or with an antitumor vaccine, respectively. Our results suggest that inhibition of NFAT/FOXP3 interaction might improve antitumor immunotherapies.
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http://dx.doi.org/10.4049/jimmunol.1402997DOI Listing
October 2015

Jarid2 is induced by TCR signalling and controls iNKT cell maturation.

Nat Commun 2014 Aug 8;5:4540. Epub 2014 Aug 8.

1] Division of Signalling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA [2] Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA.

Jarid2 is a reported component of three lysine methyltransferase complexes, polycomb repressive complex 2 (PRC2) that methylates histone 3 lysine 27 (H3K27), and GLP-G9a and SETDB1 complexes that methylate H3K9. Here we show that Jarid2 is upregulated upon TCR stimulation and during positive selection in the thymus. Mice lacking Jarid2 in T cells display an increase in the frequency of IL-4-producing promyelocytic leukemia zinc finger (PLZF)(hi) immature invariant natural killer T (iNKT) cells and innate-like CD8(+) cells; Itk-deficient mice, which have a similar increase of innate-like CD8(+) cells, show blunted upregulation of Jarid2 during positive selection. Jarid2 binds to the Zbtb16 locus, which encodes PLZF, and thymocytes lacking Jarid2 show increased PLZF and decreased H3K9me3 levels. Jarid2-deficient iNKT cells perturb Th17 differentiation, leading to reduced Th17-driven autoimmune pathology. Our results establish Jarid2 as a novel player in iNKT cell maturation that regulates PLZF expression by modulating H3K9 methylation.
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http://dx.doi.org/10.1038/ncomms5540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314221PMC
August 2014

Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation.

Nat Commun 2013 ;4:2990

1] Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA [2] Committee on Immunology, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA [3] Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA.

Atopic asthma is an inflammatory pulmonary disease associated with Th2 adaptive immune responses triggered by innocuous antigens. While dendritic cells (DCs) are known to shape the adaptive immune response, the mechanisms by which DCs promote Th2 differentiation remain elusive. Herein we demonstrate that Th2-promoting stimuli induce DC expression of IRF4. Mice with conditional deletion of Irf4 in DCs show a dramatic defect in Th2-type lung inflammation, yet retain the ability to elicit pulmonary Th1 antiviral responses. Using loss- and gain-of-function analysis, we demonstrate that Th2 differentiation is dependent on IRF4 expression in DCs. Finally, IRF4 directly targets and activates the Il-10 and Il-33 genes in DCs. Reconstitution with exogenous IL-10 and IL-33 recovers the ability of Irf4-deficient DCs to promote Th2 differentiation. These findings reveal a regulatory module in DCs by which IRF4 modulates IL-10 and IL-33 cytokine production to specifically promote Th2 differentiation and inflammation.
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http://dx.doi.org/10.1038/ncomms3990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003872PMC
July 2014

MicroRNA-directed program of cytotoxic CD8+ T-cell differentiation.

Proc Natl Acad Sci U S A 2013 Nov 25;110(46):18608-13. Epub 2013 Oct 25.

Signaling and Gene Expression Division, La Jolla Institute for Allergy and Immunology, San Diego, CA 92037.

Acquisition of effector properties is a key step in the generation of cytotoxic T lymphocytes (CTLs). Here we show that inflammatory signals regulate Dicer expression in CTLs, and that deletion or depletion of Dicer in mouse or human activated CD8(+) T cells causes up-regulation of perforin, granzymes, and effector cytokines. Genome-wide analysis of microRNA (miR, miRNA) changes induced by exposure of differentiating CTLs to IL-2 and inflammatory signals identifies miR-139 and miR-150 as components of an miRNA network that controls perforin, eomesodermin, and IL-2Rα expression in differentiating CTLs and whose activity is modulated by IL-2, inflammation, and antigenic stimulation. Overall, our data show that strong IL-2R and inflammatory signals act through Dicer and miRNAs to control the cytolytic program and other aspects of effector CTL differentiation.
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http://dx.doi.org/10.1073/pnas.1317191110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831973PMC
November 2013

Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX.

Nature 2013 May 7;497(7447):122-6. Epub 2013 Apr 7.

Division of Signaling and Gene Expression, La Jolla Institute for Allergy & Immunology, La Jolla, California 92037, USA.

TET (ten-eleven-translocation) proteins are Fe(ii)- and α-ketoglutarate-dependent dioxygenases that modify the methylation status of DNA by successively oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine, potential intermediates in the active erasure of DNA-methylation marks. Here we show that IDAX (also known as CXXC4), a reported inhibitor of Wnt signalling that has been implicated in malignant renal cell carcinoma and colonic villous adenoma, regulates TET2 protein expression. IDAX was originally encoded within an ancestral TET2 gene that underwent a chromosomal gene inversion during evolution, thus separating the TET2 CXXC domain from the catalytic domain. The IDAX CXXC domain binds DNA sequences containing unmethylated CpG dinucleotides, localizes to promoters and CpG islands in genomic DNA and interacts directly with the catalytic domain of TET2. Unexpectedly, IDAX expression results in caspase activation and TET2 protein downregulation, in a manner that depends on DNA binding through the IDAX CXXC domain, suggesting that IDAX recruits TET2 to DNA before degradation. IDAX depletion prevents TET2 downregulation in differentiating mouse embryonic stem cells, and short hairpin RNA against IDAX increases TET2 protein expression in the human monocytic cell line U937. Notably, we find that the expression and activity of TET3 is also regulated through its CXXC domain. Taken together, these results establish the separate and linked CXXC domains of TET2 and TET3, respectively, as previously unknown regulators of caspase activation and TET enzymatic activity.
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http://dx.doi.org/10.1038/nature12052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3643997PMC
May 2013

Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors.

Proc Natl Acad Sci U S A 2012 Sep 21;109(36):14532-7. Epub 2012 Aug 21.

La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.

Bromodomain-containing proteins bind acetylated lysine residues on histone tails and are involved in the recruitment of additional factors that mediate histone modifications and enable transcription. A compound, I-BET-762, that inhibits binding of an acetylated histone peptide to proteins of the bromodomain and extra-terminal domain (BET) family, was previously shown to suppress the production of proinflammatory proteins by macrophages and block acute inflammation in mice. Here, we investigated the effect of short-term treatment with I-BET-762 on T-cell function. Treatment of naïve CD4(+) T cells with I-BET-762 during the first 2 d of differentiation had long-lasting effects on subsequent gene expression and cytokine production. Gene expression analysis revealed up-regulated expression of several antiinflammatory gene products, including IL-10, Lag3, and Egr2, and down-regulated expression of several proinflammatory cytokines including GM-CSF and IL-17. The short 2-d treatment with I-BET-762 inhibited the ability of antigen-specific T cells, differentiated under Th1 but not Th17 conditions in vitro, to induce pathogenesis in an adoptive transfer model of experimental autoimmune encephalomyelitis. The suppressive effects of I-BET-762 on T-cell mediated inflammation in vivo were accompanied by decreased recruitment of macrophages, consistent with decreased GM-CSF production by CNS-infiltrating T cells. These effects were mimicked by an inhibitor of c-myc function, implicating reduced expression of c-myc and GM-CSF as one avenue by which I-BET-762 suppresses the inflammatory functions of T cells. Our study demonstrates that inhibiting the functions of BET-family proteins during early T-cell differentiation causes long-lasting suppression of the proinflammatory functions of Th1 cells.
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http://dx.doi.org/10.1073/pnas.1212264109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437860PMC
September 2012

Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice.

Proc Natl Acad Sci U S A 2011 Aug 22;108(35):14566-71. Epub 2011 Aug 22.

Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.

The Ten-Eleven-Translocation 2 (TET2) gene encodes a member of TET family enzymes that alters the epigenetic status of DNA by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Somatic loss-of-function mutations of TET2 are frequently observed in patients with diverse myeloid malignancies, including myelodysplastic syndromes, myeloproliferative neoplasms, and chronic myelomonocytic leukemia. By analyzing mice with targeted disruption of the Tet2 catalytic domain, we show here that Tet2 is a critical regulator of self-renewal and differentiation of hematopoietic stem cells (HSCs). Tet2 deficiency led to decreased genomic levels of 5hmC and augmented the size of the hematopoietic stem/progenitor cell pool in a cell-autonomous manner. In competitive transplantation assays, Tet2-deficient HSCs were capable of multilineage reconstitution and possessed a competitive advantage over wild-type HSCs, resulting in enhanced hematopoiesis into both lymphoid and myeloid lineages. In vitro, Tet2 deficiency delayed HSC differentiation and skewed development toward the monocyte/macrophage lineage. Our data indicate that Tet2 has a critical role in regulating the expansion and function of HSCs, presumably by controlling 5hmC levels at genes important for the self-renewal, proliferation, and differentiation of HSCs.
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http://dx.doi.org/10.1073/pnas.1112317108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167529PMC
August 2011

Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex.

Proc Natl Acad Sci U S A 2011 Jul 27;108(28):11381-6. Epub 2011 Jun 27.

Department of Pathology, Harvard Medical School, Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA.

Nuclear factor of activated T cells (NFAT) proteins are Ca(2+)-regulated transcription factors that control gene expression in many cell types. NFAT proteins are heavily phosphorylated and reside in the cytoplasm of resting cells; when cells are stimulated by a rise in intracellular Ca(2+), NFAT proteins are dephosphorylated by the Ca(2+)/calmodulin-dependent phosphatase calcineurin and translocate to the nucleus to activate target gene expression. Here we show that phosphorylated NFAT1 is present in a large cytoplasmic RNA-protein scaffold complex that contains a long intergenic noncoding RNA (lincRNA), NRON [noncoding (RNA) repressor of NFAT]; a scaffold protein, IQ motif containing GTPase activating protein (IQGAP); and three NFAT kinases, casein kinase 1, glycogen synthase kinase 3, and dual specificity tyrosine phosphorylation regulated kinase. Combined knockdown of NRON and IQGAP1 increased NFAT dephosphorylation and nuclear import exclusively after stimulation, without affecting the rate of NFAT rephosphorylation and nuclear export; and both NRON-depleted T cells and T cells from IQGAP1-deficient mice showed increased production of NFAT-dependent cytokines. Our results provide evidence that a complex of lincRNA and protein forms a scaffold for a latent transcription factor and its regulatory kinases, and support an emerging consensus that lincRNAs that bind transcriptional regulators have a similar scaffold function.
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http://dx.doi.org/10.1073/pnas.1019711108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136327PMC
July 2011

Structure of a domain-swapped FOXP3 dimer on DNA and its function in regulatory T cells.

Immunity 2011 Apr 31;34(4):479-91. Epub 2011 Mar 31.

Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital, Boston, MA 02115, USA.

The transcription factor FOXP3 is essential for the suppressive function of regulatory T cells that are required for maintaining self-tolerance. We have solved the crystal structure of the FOXP3 forkhead domain as a ternary complex with the DNA-binding domain of the transcription factor NFAT1 and a DNA oligonucleotide from the interleukin-2 promoter. A striking feature of this structure is that FOXP3 forms a domain-swapped dimer that bridges two molecules of DNA. Structure-guided or autoimmune disease (IPEX)-associated mutations in the domain-swap interface diminished dimer formation by the FOXP3 forkhead domain without compromising FOXP3 DNA binding. These mutations also eliminated T cell-suppressive activity conferred by FOXP3, both in vitro and in a murine model of autoimmune diabetes in vivo. We conclude that FOXP3-mediated suppressor function requires dimerization through the forkhead domain and that mutations in the dimer interface can lead to the systemic autoimmunity observed in IPEX patients.
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http://dx.doi.org/10.1016/j.immuni.2011.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085397PMC
April 2011

Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2.

Nature 2010 Dec;468(7325):839-43

Department of Pathology, Harvard Medical School, Immune Disease Institute and Program in Cellular and Molecular Medicine, Children’s Hospital Boston, Boston, Massachusetts 02115, USA.

TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs.
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http://dx.doi.org/10.1038/nature09586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003755PMC
December 2010

Inducible costimulator expression regulates the magnitude of Th2-mediated airway inflammation by regulating the number of Th2 cells.

PLoS One 2009 Nov 4;4(11):e7525. Epub 2009 Nov 4.

Committee on Immunology, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.

Background: Inducible Costimulator (ICOS) is an important regulator of Th2 lymphocyte function and a potential immunotherapeutic target for allergy and asthma. A SNP in the ICOS 5' promoter in humans is associated with increased atopy and serum IgE in a founder population and increased ICOS surface expression and Th2 cytokine production from peripheral blood mononuclear cells. However, it is unknown if increased ICOS expression contributes to disease progression or is a result of disease pathology.

Methodology/principal Findings: We developed a mouse model in which ICOS surface expression levels are genetically predetermined to test our hypothesis that genetic regulation of ICOS expression controls the severity of Th2 responses in vivo. Using ICOS+/+ and ICOS+/- mice in a Th2 model of airway inflammation, we found that T cells from the ICOS+/- mice had reduced ICOS expression and decreased Th2-mediated inflammation in vivo. Although the activation status of the T cells did not differ, T cells isolated from the lungs and draining lymph nodes of ICOS+/- mice at the peak of inflammation produced less Th2 cytokines upon stimulation ex vivo. Using 4get mice, which express GFP upon IL-4 transcription, we determined that the decreased Th2 cytokines in ICOS+/- is due to reduced percentage of Th2 cells and not a defect in their ability to produce IL-4.

Conclusion: These data suggest that in both mice and humans, the level of ICOS surface expression regulates the magnitude of the in vivo Th2 response, perhaps by influencing Th2 differentiation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0007525PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768787PMC
November 2009

Fas ligand expression on T cells is sufficient to prevent prolonged airway inflammation in a murine model of asthma.

Am J Respir Cell Mol Biol 2010 Sep 23;43(3):342-8. Epub 2009 Oct 23.

Department of Medicine, University of Chicago, IL 60637, USA.

Our previous studies revealed that, in a murine model of asthma, mice that received Fas-deficient T cells developed a prolonged phase of airway inflammation, mucus production, and airway hyperreactivity that failed to resolve even 6 weeks after the last challenge. To investigate how Fas-Fas ligand (FasL) interaction occurs between T cells and other cells in vivo, Gld mice with abnormalities of the FasL signaling pathway were used. The reconstituted mice were made by transferring T cells from B6 or Gld mice to Rag(-/-) or FasL-deficient Rag(-/-) mice. We found that Rag(-/-) mice that received B6 T cells resolved the airway inflammation, whereas FasL-deficient Rag(-/-) mice that received Gld T cells developed a prolonged airway inflammation at Day 28, with decreased IFN-gamma production. Both FasL-deficient Rag(-/-) mice that received B6 T cells and Rag(-/-) mice that received Gld T cells also had completely resolved their airway inflammation by Day 28 after challenge. Interestingly, FasL-deficient Rag(-/-) mice that received Gld T cells eventually resolved airway inflammation at Day 42, with a similar level of IFN-gamma production to that of control group. These results demonstrate that FasL expression on either T cells only or non-T cells only was sufficient for the eventual resolution of airway inflammation, and the prolonged airway inflammation in FasL-deficient Rag(-/-) mice that received Gld T cells was correlated with decreased IFN-gamma production by Gld T cells.
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http://dx.doi.org/10.1165/rcmb.2008-0454OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933550PMC
September 2010

CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo.

Cell Immunol 2009 10;259(2):177-84. Epub 2009 Jul 10.

Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago, MC6076, Room M658, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.

Previous work has shown ICOS can function independently of CD28, but whether either molecule can compensate for the other in vivo is not known. Since ICOS is a potent inducer of Th2 cytokines and linked to allergy and elevated serum IgE in humans, we hypothesized that augmenting ICOS costimulation in murine allergic airway disease may overcome CD28 deficiency. While ICOS was expressed on T cells from CD28(-/-) mice, Th2-mediated airway inflammation was not induced in CD28(-/-) mice by increased ICOS costimulation. Further, we determined if augmenting CD28 costimulation could compensate for ICOS deficiency. ICOS(-/-) mice had a defect in airway eosinophilia that was not overcome by augmenting CD28 costimulation. CD28 costimulation also did not fully compensate for ICOS for antibody responses, germinal center formation or the development of follicular B helper T cells. CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo.
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http://dx.doi.org/10.1016/j.cellimm.2009.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748173PMC
October 2009

Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1.

Science 2009 May 16;324(5929):930-5. Epub 2009 Apr 16.

Department of Pathology, Harvard Medical School and Immune Disease Institute, 200 Longwood Avenue, Boston, MA 02115, USA.

DNA cytosine methylation is crucial for retrotransposon silencing and mammalian development. In a computational search for enzymes that could modify 5-methylcytosine (5mC), we identified TET proteins as mammalian homologs of the trypanosome proteins JBP1 and JBP2, which have been proposed to oxidize the 5-methyl group of thymine. We show here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro. hmC is present in the genome of mouse embryonic stem cells, and hmC levels decrease upon RNA interference-mediated depletion of TET1. Thus, TET proteins have potential roles in epigenetic regulation through modification of 5mC to hmC.
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http://dx.doi.org/10.1126/science.1170116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715015PMC
May 2009

Orphans against autoimmunity.

Immunity 2008 Aug;29(2):167-8

Department of Pathology, Harvard Medical School and Immune Disease Institute, 200 Longwood Avenue, Boston, MA 02115, USA.

In this issue of Immunity, Hermann-Kleiter et al. (2008) identify a nuclear orphan receptor, NR2F6, as a negative regulator of the T helper 17 cell subset and report that NR2F6-deficient mice develop late-onset autoimmune disease.
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http://dx.doi.org/10.1016/j.immuni.2008.07.008DOI Listing
August 2008

ICOS costimulation expands Th2 immunity by augmenting migration of lymphocytes to draining lymph nodes.

J Immunol 2008 Jul;181(2):1019-24

Department of Medicine, Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.

The T cell costimulatory molecule ICOS regulates Th2 effector function in allergic airway disease. Recently, several studies with ICOS(-/-) mice have also demonstrated a role for ICOS in Th2 differentiation. To determine the effects of ICOS on the early immune response, we investigated augmenting ICOS costimulation in a Th2-mediated immune response to Schistosoma mansoni Ags. We found that augmenting ICOS costimulation with B7RP-1-Fc increased the accumulation of T and B cells in the draining lymph nodes postimmunization. Interestingly, the increased numbers were due in part to increased migration of undivided Ag-specific TCR transgenic T cells and surprisingly B cells, as well as non-TCR transgenic T cells. B7RP-1-Fc also increased the levels of the chemokines CCL21 and CXCL13 in the draining lymph node, suggesting ICOS costimulation contributes to migration by direct or indirect effects on dendritic cells, stromal cells and high endothelial venules. Further, the effects of B7RP-1-Fc were not dependent on immunization. Our data support a model in which ICOS costimulation augments the pool of lymphocytes in the draining lymph nodes, leading to an increase in the frequency of potentially reactive T and B cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2560985PMC
http://dx.doi.org/10.4049/jimmunol.181.2.1019DOI Listing
July 2008

Signaling through Fc gamma RIII is required for optimal T helper type (Th)2 responses and Th2-mediated airway inflammation.

J Exp Med 2007 Aug 30;204(8):1875-89. Epub 2007 Jul 30.

Committee on Immunology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.

Although inhibitory Fc gamma receptors have been demonstrated to promote mucosal tolerance, the role of activating Fc gamma receptors in modulating T helper type (Th)2-dependent inflammatory responses characteristic of asthma and allergies remains unclear. Here, we demonstrate that signaling via activating Fc gamma receptors in conjunction with Toll-like receptor 4 stimulation modulated cytokine production from bone marrow-derived dendritic cells (DCs) and augmented their ability to promote Th2 responses. Ligation of the low affinity receptor Fc gamma RIII was specifically required for the enhanced Th2 responses, as Fc gamma RIII(-/-) DCs failed to augment Th2-mediated airway inflammation in vivo or induce Th2 differentiation in vitro. Further, Fc gamma RIII(-/-) mice had impaired Th2 cytokine production and exhibited reduced airway inflammation, whereas no defect was found in Fc gamma RI(-/-) mice. The augmentation of Th2 immunity was regulated by interleukin 10 production from the DCs but was distinct and independent of the well-established role of Fc gamma RIII in augmenting antigen presentation. Thus, our studies reveal a novel and specific role for Fc gamma RIII signaling in the regulation of Th cell responses and suggest that in addition to immunoglobulin (Ig)E, antigen-specific IgG also contributes to the pathogenesis of Th2-mediated diseases such as asthma and allergies.
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http://dx.doi.org/10.1084/jem.20061134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118666PMC
August 2007

Signaling through CD43 regulates CD4 T-cell trafficking.

Blood 2007 Oct 16;110(8):2974-82. Epub 2007 Jul 16.

Committee on Immunology, University of Chicago, IL 60637, USA.

The mucin-like protein CD43 is excluded from the immune synapse, and regulates T-cell proliferation as well as T-cell migration. While the CD43 cytoplasmic domain is necessary for regulation of T-cell activation and proliferation, the mechanism via which CD43 regulates trafficking is not well defined. To investigate whether CD43 phosphorylation regulates its function in T cells, we used tandem mass spectrometry and identified Ser76 in murine CD43 as a previously unidentified site of basal phosphorylation. Interestingly, mutation of this single serine to alanine greatly diminishes T-cell trafficking to the lymph node, while CD43 exclusion and CD43-mediated regulation of T-cell proliferation remain intact. Furthermore, the CD43 extracellular domain was also required for T-cell trafficking, providing a hitherto unknown function for the extracellular domain, and suggesting that the extracellular domain may be required to transduce signals via the cytoplasmic domain. These data reveal a novel mechanism by which CD43 regulates T-cell function, and suggest that CD43 functions as a signaling molecule, sensing extracellular cues and transducing intracellular signals that modulate T-cell function.
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http://dx.doi.org/10.1182/blood-2007-01-065276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2018673PMC
October 2007

Regulation of T:B cell interactions by the inducible costimulator molecule: does ICOS "induce" disease?

Clin Immunol 2006 Oct 21;121(1):13-8. Epub 2006 Jun 21.

Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago MC 6076, 5841 S. Maryland Ave, Chicago, IL 60637, USA.

The Inducible Costimulator molecule (ICOS), a member of the CD28 family of costimulatory molecules, was identified in 1999 as a molecule expressed primarily on activated human T cells. Induced upon activation, ICOS appears to be an ideal target for modifying T-cell-mediated immune responses. ICOS was also found to be highly expressed on germinal center T cells, suggesting that ICOS was involved in T:B cell interactions. While ICOS has subsequently been shown to be important for both Th1 and Th2 cell activation and effector function, a central role for ICOS in the generation and maintenance of humoral immunity is emerging. In this review, we summarize the evidence that the level of ICOS expression regulates T-cell-dependent B cell responses and propose a model for the role of ICOS in diseases characterized by dysregulated humoral immunity.
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http://dx.doi.org/10.1016/j.clim.2006.04.574DOI Listing
October 2006

Cutting edge: polymorphisms in the ICOS promoter region are associated with allergic sensitization and Th2 cytokine production.

J Immunol 2005 Aug;175(4):2061-5

Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago, IL 60637, USA.

The establishment of ICOS as an important regulator of Th2 development and effector function makes the ICOS locus an attractive candidate for Th2-mediated diseases, such as asthma and allergy. In evaluation of this candidate locus in humans, we identified 11 variants and determined that two in the putative promoter region are significantly associated with allergic sensitization and serum IgE levels. In addition, cultures of activated PBMCs from individuals homozygous for the associated polymorphisms produced increased levels of the Th2 cytokines, IL-4, IL-5, and IL-13, as well as TNF-alpha compared with controls. One of the polymorphisms, -1413G/A, demonstrated differential NF-kappaB binding in mobility shift analysis, suggesting that this polymorphism has functional consequences. Overall, these data demonstrate that ICOS is a susceptibility gene for allergic sensitization, perhaps through the promotion of Th2 differentiation.
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http://dx.doi.org/10.4049/jimmunol.175.4.2061DOI Listing
August 2005