Article

Fields, P. E., Kim, S. T. & Flavell, R. A. Cutting edge: changes in histone acetylation at the IL-4 and IFN- loci accompany TH1/TH2 differentiation. J. Immunol. 169, 647-650

Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
The Journal of Immunology (Impact Factor: 5.36). 08/2002; 169(2):647-50. DOI: 10.4049/jimmunol.169.2.647
Source: PubMed

ABSTRACT Peripheral T cell differentiation is accompanied by chromatin changes at the signature cytokine loci. Using chromatin immunoprecipitation we demonstrate that profound increases in histone acetylation occur at the IFN-gamma and IL-4 loci during Th1/Th2 differentiation. These changes in histone acetylation status are locus and lineage specific, and are maintained by the transcription factors Tbet and GATA3 in a STAT-dependent manner. Our results suggest a model of cytokine locus activation in which TCR signals initiate chromatin remodeling and locus opening in a cytokine-independent fashion. Subsequently, cytokine signaling reinforces polarization by expanding and maintaining the accessible state at the relevant cytokine locus (IL-4 or IFN-gamma). In this model, GATA3 and Tbet serve as transcriptional maintenance factors, which keep the locus accessible to the transcriptional machinery.

Download full-text

Full-text

Available from: Richard A Flavell, Jul 28, 2015
0 Followers
 · 
104 Views
  • Source
    • "The MP-based vaccine also induced relatively low Th2 type IL-4 cytokine expression, in all three routes compared to Th1-type cytokine induction. This may be due to the antagonism that occurs between Th1 and Th2 cytokines, where high Th1 cytokine levels can suppress IL-4 secretion [57]. The alum-based vaccine induced high IL-10 expression levels compared to the MP-based vaccine, when administered via the s.c. and i.p. routes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recombinant viral subunit-based vaccines have gained increasing attention due to their enhanced safety over the classic live-attenuated or inactivated vaccines. The low immunogenicity of the subunit antigen alone, however, requires the addition of an adjuvant to induce immunity. Particulate-based delivery systems have great potential for developing new vaccine adjuvants, compared to traditional aluminum-based saline adjuvants. The physicochemical properties of particulate vaccines have been extensively investigated; however, few studies have focused on how the administration route of various adjuvant-antigen combinations impacts the efficacy of the immune response. Here, for the first time, the viral Hepatitis B surface antigen (HBsAg) was combined with aluminum-based or cationic-microsphere (MP) based adjuvants to investigate the characteristics of immune responses elicited after immunization via the subcutaneous, intramuscular, or intraperitoneal routes respectively. In vitro, the MP-based vaccine significantly increased dendritic cell (DC) activation with up-regulated CD40 and CD80 expression and IL-12 production compared to alum-based vaccine. After immunization, both MP and alum-based vaccines produced increased IgG titers in mice. The administration route of these vaccines did influenced immune responses. The MP-based vaccine delivered via the intramuscular route yielded the highest levels of the IgG2a isotype. The alum-based vaccine, delivered via the same route, produced an IgG1-dominated humoral immune response. Moreover, subcutaneous and intramuscular immunizations with MP-based vaccine augmented Granzyme B, Th1-type cytokines (IL-2, IL-12, and IFN-gamma), and Th2 cytokine IL-4 secretions. These results demonstrate that MP-based vaccines have the capacity to induce higher cellular and humoral immune response especially via an intramuscular administration route than an alum-based vaccine.
    International Immunopharmacology 10/2014; 23(2). DOI:10.1016/j.intimp.2014.10.010 · 2.71 Impact Factor
  • Source
    • "Permissive modifications render the gene locus more accessible to transcription factors, whereas repressive modifications make the gene locus less accessible. Permissive modifications include demethylation of CpG islands in the regulatory regions of a gene, acetylation of the 9th and 14th lysine residues of histone 3 (H3K9/14ac), and dimethylation of the 4th lysine residue of H3 (H3K4me2) [3] [4] [5] [6] [7]. Repressive modifications include methylation of the 9th lysine residue of H3 (H3K9me) [6], methylation of the 27th lysine residue of H3 (H3K27me) [8] and methylation of the 36th lysine residue of H3 (H3K36me) [2]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In order to develop the most effective T helper type-1 (Th1) immunity, naïve CD4(+) T cells must acquire the capacity to express IFN-γ while silencing T helper type-2 (Th2) cytokine-producing potential. An Il4 gene silencer has been described. However, it is not completely understood how the silencer works. In this study, we examine whether IFN-γ can suppress permissive chromatin remodeling of regulatory region of the Il4 gene. We demonstrate that IFN-γ suppresses H3K4 dimethylation at the intronic enhancer region of the Il4 gene. The IFN-γ-mediated suppression of permissive chromatin remodeling is IFN-γ receptor-, STAT1-, and T-bet-dependent. Our study reveals a novel mechanism of how Th1 cells silence the Il4 gene.
    Cytokine 03/2013; 62(1). DOI:10.1016/j.cyto.2013.02.010 · 2.87 Impact Factor
  • Source
    • "Azacitidine treatment may therefore enhance the number of FOXP3 + Treg which subsequently inhibit inflammatory cytokine production by Th cells and, as such, azacitidine treatment may be beneficial in low-risk MDS in which Treg control appears to be lacking. Furthermore, up-regulation of killercell immunoglobulin-like receptors (KIRs) on NK cells by azacitidine leads to reduced cytotoxicity, which may also be of benefit in low-risk disease (Gao et al, 2009) On the other hand, demethylating agents enhance IFN-c production, either directly through demethylation of the IFNG promoter or also via KIR up-regulation, which may be harmful in low-risk disease (Fields et al, 2002; Yano et al, 2003; Liu et al, 2009). How these in vitro effects relate to the in vivo effects of azacitidine treatment remains to be established. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The myelodysplastic syndromes (MDS) constitute a group of heterogeneous clonal haemopoietic stem cell disorders, characterized by ineffective and dysplastic haematopoiesis with varying degrees of peripheral cytopenia. Low-risk MDS is characterized by increased apoptosis in the bone marrow (BM) with autoimmune characteristics whereas the advanced or high-risk stages involve immune evasion and secondary DNA damage, giving cells growth potential to progress into acute myeloid leukaemia (AML). Nevertheless, the causes of MDS remain poorly defined and it is not clear how the disease progresses from an early stage to advanced MDS and AML. Although there are clear indications for a role of the immune system, the exact mechanism by which the immune response contributes to the progression is not yet clear. New insights into the pathophysiology of MDS with regard to the immune system will be instrumental for the development of novel patient-oriented therapies. This review is focused on the role of immune responses in MDS and the implications for the development of novel immune therapies.
    British Journal of Haematology 06/2011; 153(5):568-81. DOI:10.1111/j.1365-2141.2011.08683.x · 4.96 Impact Factor
Show more