IL-4 Signaling, Gene Transcription Regulation, and the Control of Effector T Cells

ArticleinImmunologic Research 23(2-3):179-91 · February 2001with8 Reads
DOI: 10.1385/IR:23:2-3:179 · Source: PubMed
The central goal of our laboratory is to understand the regulation of lymphoid cells through molecular mechanisms of signal transduction and transcriptional control. A long-standing focus has been on changes that influence the effector function of mature lymphocytes. Work in the laboratory is oriented toward the identification of new regulatory mechanisms using cell lines and primary cells, and the validation of these in vitro findings in mouse models of immune responses and diseases. In this review, we summarize key insights into the regulation of T helper cell function during the phase of immunity where effector responses arise de novo. Particular interest has been centered on cytokine gene regulation as part of T cell differentiation into the Th1 and Th2 subsets. Information on IL-4 receptor signaling and the role of NF-kappaB transcription factors is reviewed. Our more recent work is designed to understand how regulation at the Th1/2 effector stages is related to the control of memory T cell survival, immune recall responses, and the role of these responses in immune-mediated disease.
    • "Consistently, FA increased the release of Th2 cytokines such as IL-4, IL-5 and IL-13 from MLN cells. Although IL-4 plays an essential role in the antibody class-switching to IgE synthesis [34,35], it was not lowered in MLN from cocoa-fed animals, which agrees with previous studies on cocoa-fed allergic rats [12]. Interestingly, both cocoa diets showed a protective role against the increase of other Th2-cytokines such as IL-5 and IL-13, and the CC diet also decreased the release of the Th1-cytokines IL-1α, IL-1β and IFN-γ from MLN cells. "
    [Show abstract] [Hide abstract] ABSTRACT: Previous studies have demonstrated that cocoa intake decreased Th2 immune-related antibodies in rats. In consequence, we aimed to study in depth this cocoa action, particularly assessing its effect on a rat model of food allergy (FA) and also on an anaphylactic response. The involvement of the intestinal immune system was analyzed to allow the action mechanisms to be investigated. The role of cocoa flavonoids in the antiallergic properties of cocoa was also established. Brown Norway rats were fed either a reference diet or diets containing conventional cocoa (CC) or nonfermented cocoa (NFC). FA to ovalbumin (OVA) was induced and, later, an anaphylactic response was provoked. As expected, the synthesis of anti-OVA IgE and other Th2-related antibodies was inhibited by CC diet. In addition, the release of mast cell protease II after anaphylaxis was partially prevented by CC, although other variables were not modified. The CC diet also attenuated the increase of some Th2-related cytokines released from mesenteric lymph node and spleen cells, and modulated the intestinal gene expression of molecules involved in allergic response. These results demonstrated the local and systemic influence of CC diet. The effects of the NFC diet were weaker than those of CC, suggesting that cocoa components other than flavonoids play a role in cocoa's action. In conclusion, by acting on intestinal and systemic immune functions, a cocoa-enriched diet in rats exhibited a protective effect against FA and partially against anaphylaxis, making this a food of high interest to the fields of health and immunonutrition.
    Article · Oct 2015
    • "Interestingly, the conventional immunological function of IL-4 is to stimulate Th 2 type immune effectors and to suppress Th 1 immunity. However, the IL-4 bearing CYT-IVAC, which induced elevated IgG 2a antibody titers, appears to be able to polarize immune effectors in a different manner than that described for soluble IL-451525354. Other groups have reported that IL-4 in a membrane-bound form and in a highly localized environment can induce IL-12 production , a potent Th 1 inducer, in APCs55565758. "
    [Show abstract] [Hide abstract] ABSTRACT: Influenza epidemics continue to cause morbidity and mortality within the human population despite widespread vaccination efforts. This, along with the ominous threat of an avian influenza pandemic (H5N1), demonstrates the need for a much improved, more sophisticated influenza vaccine. We have developed an in vitro model system for producing a membrane-bound Cytokine-bearing Influenza Vaccine (CYT-IVAC). Numerous cytokines are involved in directing both innate and adaptive immunity and it is our goal to utilize the properties of individual cytokines and other immunomodulatory proteins to create a more immunogenic vaccine. We have evaluated the immunogenicity of inactivated cytokine-bearing influenza vaccines using a mouse model of lethal influenza virus challenge. CYT-IVACs were produced by stably transfecting MDCK cell lines with mouse-derived cytokines (GM-CSF, IL-2 and IL-4) fused to the membrane-anchoring domain of the viral hemagglutinin. Influenza virus replication in these cell lines resulted in the uptake of the bioactive membrane-bound cytokines during virus budding and release. In vivo efficacy studies revealed that a single low dose of IL-2 or IL-4-bearing CYT-IVAC is superior at providing protection against lethal influenza challenge in a mouse model and provides a more balanced Th1/Th2 humoral immune response, similar to live virus infections. We have validated the protective efficacy of CYT-IVACs in a mammalian model of influenza virus infection. This technology has broad applications in current influenza virus vaccine development and may prove particularly useful in boosting immune responses in the elderly, where current vaccines are minimally effective.
    Full-text · Article · May 2009
    • "Both pathways are required for the proliferative activity of CD4 T cells induced by IL-4, but they do not seem to participate in the IL-4-dependent rescue from apoptosis [16]. IL-4 can also induce a Jak3-dependent activation of STAT1 and STAT5, but this effect appears to be observed only in differentiated CD4 Th2 cells17181920. Although the effects of IL-4 on CD4 T cells have been examined extensively, the signaling events induced by IL-4 on CD8 T cells have not been studied, in spite of increasing evidence indicating an important role for this cytokine in CD8 T cell function and differentiation. "
    [Show abstract] [Hide abstract] ABSTRACT: IL-4 has distinct effects on the differentiation and functional properties of CD8+ T cells. In vivo studies have shown that it is critical for the development of protective memory responses against tumors and infections by Leishmania and Plasmodium parasites. The intracellular signaling events mediated by IL-4/IL-4 receptor (IL-4R) interactions on CD4+ T cells have been studied extensively; however, the nature of IL-4-induced signaling on CD8+ T cells has not been characterized. Using naïve, activated, as well as differentiated CD8+ T cells, we show that IL-4 has a strong in vivo and in vitro antiapoptotic effect on activated and resting CD8+ T cells. We demonstrate that IL-4 induces the phosphorylation of the IL-4R, which is followed by the activation of at least two distinct intracellular signaling cascades: the Jak1/STAT6 and the insulin receptor substrate/PI-3K/protein kinase B pathways. We also found that IL-4 induces the Jak3-mediated phosphorylation and nuclear migration of STAT1, STAT3, and STAT5 in naïve, activated, as well as differentiated, IFN-gamma-producing CD8+ T cells. The induction of this broad signaling activity in CD8+ T cells coincides with a transcriptional activity of suppressors of cytokine signaling genes, which are decreased significantly in comparison with CD4+ T cells. To our knowledge, this report constitutes the first comprehensive analysis of the signaling events that shape CD8+ T cell responses to IL-4.
    Full-text · Article · May 2007
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