Mina, an Il4 repressor, controls T helper type 2 bias.
Ontology highlight
ABSTRACT:
SUBMITTER: Okamoto M
PROVIDER: S-EPMC2825757 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Immune cells constitute a large fraction of the tumor microenvironment and modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL4 in particular is upregulated. Here, we demonstrate that T follicular helper (Tfh) cells arise in tumor-draining lymph nodes where they produce an abundance of IL4. Deletion of IL4-expressing Tfh cells improves antitumor immunity, delays tumor growth, and reduces the generation of immunosuppressive myeloid cells in the lymph nodes. These findings suggest that IL4 from Tfh cells affects antitumor immunity and constitutes an attractive therapeutic target to reduce immunosuppression in the tumor microenvironment, and thus enhance the efficacy of cancer immunotherapy. Cancer Immunol Res; 5(1); 61-71. ©2016 AACR.
| S-EPMC6385600 | biostudies-literature
Project description:Interferon gamma (IFN gamma) is the hallmark cytokine produced by T helper type 1 (Th1) cells, whereas interleukin (IL)-4 is the hallmark cytokine produced by Th2 cells. Although previous studies have revealed the roles of cytokine signaling and of transcription factors during differentiation of Th1 or Th2 cells, it is unclear how the exclusive expression pattern of each hallmark cytokine is established. The DNaseI hypersensitivity site IV within the mouse Il4 locus plays an important role in the repression of Il4 expression in Th1 cells, and it has been named the Il4 silencer. Using Cbf beta- or Runx3-deficient T cells, we show that loss of Runx complex function results in derepression of IL-4 in Th1 cells. Binding of Runx complexes to the Il4 silencer was detected in naive CD4(+) T cells and Th1 cells, but not in Th2 cells. Furthermore, enforced expression of GATA-3 in Th1 cells inhibited binding of Runx complexes to the Il4 silencer. Interestingly, T cell-specific inactivation of the Cbf beta gene in mice led to elevated serum immunoglobulin E and airway infiltration. These results demonstrate critical roles of Runx complexes in regulating immune responses, at least in part, through the repression of the Il4 gene.
| S-EPMC2118685 | biostudies-literature
Project description:Type 2 T helper (T(H)2) cells are critical for the development of allergic immune responses; however, the molecular mechanism controlling their effector function is still largely unclear. Here, we report that the transcription factor NFIL3/E4BP4 regulates cytokine production and effector function by T(H)2 cells. NFIL3 is highly expressed in T(H)2 cells but much less in T(H)1 cells. Production of interleukin (IL)-13 and IL-5 is significantly increased in Nfil3(-/-) T(H)2 cells and is decreased by expression of NFIL3 in wild-type T(H)2 cells. NFIL3 directly binds to and negatively regulates the Il13 gene. In contrast, IL-4 production is decreased in Nfil3(-/-) T(H)2 cells. Increased IL-13 and IL-5 together with decreased IL-4 production by antigen-stimulated splenocytes from the immunized Nfil3(-/-) mice was also observed. The ability of NFIL3 to alter T(H)2 cytokine production is a T-cell intrinsic effect. Taken together, these data indicate that NFIL3 is a key regulator of T(H)2 responses.
| S-EPMC3098483 | biostudies-literature
Project description:Nuclear factor of activated T cell (NFAT) transcription factors are key regulators of gene transcription within immune cells. The NFAT-interacting protein, (NIP45), augments NFAT-driven IL-4 expression by a mechanism that relies on arginine methylation. To establish the function of NIP45 in vivo, we generated mice with a targeted deletion of the gene encoding this cofactor. NIP45-deficient T helper cells displayed profound defects in the expression of NFAT-regulated cytokine genes, including IL-4. Whereas NIP45 deficiency does not interfere with T helper cell NFAT activation or lineage-specific transcription-factor expression, NIP45 acts as an enhancer for the assembly of protein arginine methyltransferase 1 and the protein arginine methyltransferase 1-linked histone 4 arginine 3 methylation with the IL-4 promoter. Our study reveals an essential role for NIP45 in promoting robust cytokine expression in vivo, which is required for the efficient handling of parasites. We propose that NIP45 acts as a molecular rheostat serving to amplify the type-2 immune response.
| S-EPMC2840445 | biostudies-other
Project description:The spatiotemporal distribution of cytokines orchestrates immune responses in vivo, yet the underlying mechanisms remain to be explored. We showed here that the spatial distribution of interleukin-4 (IL4) in invariant natural killer T (iNKT) cells regulated crosstalk between iNKT cells and dendritic cells (DCs) and controlled iNKT cell-mediated T-helper type 1 (Th1) responses. The persistent polarization of IL4 induced by strong lipid antigens, that is, α-galactosylceramide (αGC), caused IL4 accumulation at the immunological synapse (IS), which promoted the activation of the IL4R-STAT6 (signal transducer and activator of transcription 6) pathway and production of IL12 in DCs, which enhanced interferon-γ (IFNγ) production in iNKT cells. Conversely, the nonpolarized secretion of IL4 induced by Th2 lipid antigens with a short or unsaturated chain was incapable of enhancing this iNKT cell-DC crosstalk and thus shifted the immune response to a Th2-type response. The nonpolarized secretion of IL4 in response to Th2 lipid antigens was caused by the degradation of Cdc42 in iNKT cells. Moreover, reduced Cdc42 expression was observed in tumor-infiltrating iNKT cells, which impaired IL4 polarization and disturbed iNKT cell-DC crosstalk in tumors.
| S-EPMC7192838 | biostudies-literature
Project description:Il4 and Il13 encode the canonical T helper 2 (TH2) cytokines responsible both for promoting immune responses against extracellular pathogens and, when misregulated, causing allergic and autoimmune disease. The expression potential of these genes undergoes developmentally programmed repression and enhancement during commitment of naïve CD4+ T cells to the mature T helper 1 (TH1) and TH2 fates, respectively. Thus, like the globin locus, the TH2 cytokine locus provides a highly tractable system to study a developmental fate choice leading to alternative transcriptional states of either silence or permissivity. We used quantitative chromatin immunoprecipitation and RT-PCR to correlate changes in the transcriptional states of Il4 and Il13 with markers of permissive chromatin across the Il4-Il13 locus in naïve CD4+ T cells undergoing TH1 and TH2 differentiation. We provide evidence that DNaseI hypersensitive site V in the Il4 3' enhancer is the likely target for signals maintaining Il4 and Il13 transcriptional permissivity in naïve cells. We also demonstrate rapid acquisition of differences in H3 acetylation between TH1- and TH2-primed cells, indicating a developmentally early role for cytokine signaling in the process of TH cell fate determination. Finally, we show that transcriptional repression correlates with the disappearance of permissive H3 modifications from everywhere in the Il4-Il13 locus except hypersensitive site IV, suggesting a critical role for this element in the maintenance of transcriptional repression. Our findings are consistent with a progressive regulatory element activation/deactivation model of TH1/TH2 development.
| S-EPMC509214 | biostudies-literature
Project description:Follicular helper T cells (Tfh cells) are the major producers of interleukin-4 (IL-4) in secondary lymphoid organs where humoral immune responses develop. Il4 regulation in Tfh cells appears distinct from the classical T helper 2 (Th2) cell pathway, but the underlying molecular mechanisms remain largely unknown. We found that hypersensitivity site V (HS V; also known as CNS2), a 3' enhancer in the Il4 locus, is essential for IL-4 production by Tfh cells. Mice lacking HS V display marked defects in type 2 humoral immune responses, as evidenced by abrogated IgE and sharply reduced IgG1 production in vivo. In contrast, effector Th2 cells that are involved in tissue responses were far less dependent on HS V. HS V facilitated removal of repressive chromatin marks during Th2 and Tfh cell differentiation and increased accessibility of the Il4 promoter. Thus, Tfh and Th2 cells utilize distinct but overlapping molecular mechanisms to regulate Il4, a finding with important implications for understanding the molecular basis of allergic diseases.
| S-EPMC3288297 | biostudies-literature
Project description:T follicular helper (TFH) cells are a distinct type of CD4+ T cells that are essential for most antibody and B lymphocyte responses. TFH cell regulation and dysregulation is involved in a range of diseases. Bcl-6 is the lineage-defining transcription factor of TFH cells and its activity is essential for TFH cell differentiation and function. However, how Bcl-6 controls TFH biology has largely remained unclear, at least in part due to the intrinsic challenges of connecting repressors to gene upregulation in complex cell types with multiple possible differentiation fates. Multiple competing models were tested here by a series of experimental approaches to determine that Bcl-6 exhibits negative autoregulation and controls pleiotropic attributes of TFH differentiation and function, including migration, costimulation, inhibitory receptors and cytokines, via multiple repressor-of-repressor gene circuits.
| S-EPMC7449381 | biostudies-literature
Project description:SerpinB1, a protease inhibitor and neutrophil survival factor, was recently linked with IL-17-expressing T cells. Here, we show that serpinB1 (Sb1) is dramatically induced in a subset of effector CD4 cells in experimental autoimmune encephalomyelitis (EAE). Despite normal T cell priming, Sb1 -/- mice are resistant to EAE with a paucity of T helper (TH) cells that produce two or more of the cytokines, IFNγ, GM-CSF, and IL-17. These multiple cytokine-producing CD4 cells proliferate extremely rapidly; highly express the cytolytic granule proteins perforin-A, granzyme C (GzmC), and GzmA and surface receptors IL-23R, IL-7Rα, and IL-1R1; and can be identified by the surface marker CXCR6. In Sb1 -/- mice, CXCR6+ TH cells are generated but fail to expand due to enhanced granule protease-mediated mitochondrial damage leading to suicidal cell death. Finally, anti-CXCR6 antibody treatment, like Sb1 deletion, dramatically reverts EAE, strongly indicating that the CXCR6+ T cells are the drivers of encephalitis.
| S-EPMC6789640 | biostudies-literature
Project description:Obstructive and nonobstructive forms of hydronephrosis (increased diameter of the renal pelvis and calyces) and hydroureter (dilatation of the ureter) are the most frequently detected antenatal abnormalities, yet the underlying molecular mechanisms are largely undefined. Hedgehog (Hh) proteins control tissue patterning and cell differentiation by promoting GLI-dependent transcriptional activation and by inhibiting the processing of GLI3 to a transcriptional repressor. Genetic mutations that generate a truncated GLI3 protein similar in size to the repressor in humans with Pallister-Hall syndrome (PHS; a disorder whose characteristics include renal abnormalities) and hydroureter implicate Hh-dependent signaling in ureter morphogenesis and function. Here, we determined that Hh signaling controls 2 cell populations required for the initiation and transmission of coordinated ureter contractions. Tissue-specific inactivation of the Hh cell surface effector Smoothened (Smo) in the renal pelvic and upper ureteric mesenchyme resulted in nonobstructive hydronephrosis and hydroureter characterized by ureter dyskinesia. Mutant mice had reduced expression of markers of cell populations implicated in the coordination of unidirectional ureter peristalsis (specifically, Kit and hyperpolarization-activation cation-3 channel [Hcn3]), but exhibited normal epithelial and smooth muscle cell differentiation. Kit deficiency in a mouse model of PHS suggested a pathogenic role for GLI3 repressor in Smo-deficient embryos; indeed, genetic inactivation of Gli3 in Smo-deficient mice rescued their hydronephrosis, hydroureter, Kit and Hcn3 expression, and ureter peristalsis. Together, these data demonstrate that Hh signaling controls Kit and Hcn3 expression and ureter peristalsis.
| S-EPMC3049374 | biostudies-literature