Evidence of GATA-3-dependent Th2 commitment during the in vivo immune response.

Department of Microbiology, Kitasato University School of Medicine, Sagamihara, 228-8555 Kanagawa, Japan.
International Immunology (Impact Factor: 2.54). 02/2004; 16(1):179-87.
Source: PubMed


The transcription factor GATA-3 has been shown to play an important role for the in vitro induction of T(h)2 cells. To clarify how the in vivo immune response is governed under GATA-3 function, we generated double-transgenic mice by crossing GATA-3 transgenic mice with ovalbumin (OVA)-specific TCR transgenic mice. After immunization with OVA, the double-transgenic mice showed increased expression of GATA-3 in antigen-reactive fresh CD4(+) T cells, and higher production of IL-5 and IL-13 in cultured spleen cells in the presence of cognate antigen without any polarizing conditions for T(h)2 cells. Moreover, the immunized double-transgenic mice showed a higher increase of in vivo secretion of IL-5 and IL-13 in bronchoalveolar lavage fluid after OVA aerosol challenging. The serum levels of OVA-specific IgG1, IgE and IgA antibodies were much higher in the immunized double-transgenic mice than TCR transgenic mice. These findings provide direct evidence that antigen-stimulated CD4(+) T cells in the immunized mice have already been committed into T(h)2 cells producing IL-5 and IL-13 selectively through enhanced GATA-3 expression in vivo, thereby inducing higher production of antigen-specific antibody for three isotypes other than IgM.

Download full-text


Available from: Nobunao Ikewaki, Mar 25, 2015
  • Source
    • "Primer sequences for mouse IL-17A, IL-17F. IL-21, IL-22, IL-23R, ABCA1, ABCG1, GATA3, T-bet, IL-4, and Foxp3 have been previously described [5], [26], [27], [28]. The level of mRNA expression was normalized to that of GAPDH mRNA expression. "
    [Show abstract] [Hide abstract]
    ABSTRACT: T(H)17 cells, which require the expression of both retinoic acid receptor-related orphan receptors α and γt (RORαand RORγt) for full differentiation and function, have been implicated as major effectors in the pathogenesis of inflammatory and autoimmune diseases. We recently demonstrated that the Liver X Receptor (LXR) agonist, T0901317 (T09), also displays high-affinity RORα and RORγ inverse activity, potentially explaining its effectiveness in various T(H)17-mediated autoimmune disease models. However, recent studies suggest that in conjunction with the RORs, LXR mediates a negative regulatory effect on T(H)17 cell differentiation. Since T09 acts on both LXRs and RORs, it presents as a valuable tool to understand how compounds with mixed pharmacology affect potential pathological cell types. Therefore, using T09, we investigated the mechanism by which the LXRs and RORs affect T(H)17 cell differentiation and function. Here we demonstrate that T09 activity at RORα and γ, not LXR, is facilitating the inhibition of T(H)17 cell differentiation and function. We also demonstrate that LXR activity inhibits the differentiation and function of T(H)1, T(H)2 and iT(reg) cells. Finally, T09 inhibited T cell proliferation and induced cell death. These data help explain much of the efficacy of T09 in inflammatory models and suggest that the generation of synthetic ligands with graded, combined LXR and ROR activity may hold utility in the treatment of inflammatory and autoimmune diseases where targeting both T(H)17 and T(H)1 cells is required.
    PLoS ONE 09/2012; 7(9):e46615. DOI:10.1371/journal.pone.0046615 · 3.23 Impact Factor
  • Source
    • "Since IL-10 is involved in immune reactions in vivo (Connors et al., 1994), we have induced allergic reactions in GATA-3 Tg mice using IL-10 to examine the possibility of gene therapy against Th2-type immunity. We induced OVA-specific inflammatory reactions in GATA-3 mice that enhanced the Th2-type immune response (Tamauchi et al. 2004). A previous report showed that the instillation of IL-10 protein into the lung also suppresses eosinophilic airway inflammation (Nakagome et al. 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Interleukin-10 was originally described as a factor that inhibits cytokine production by murine Th1 clones. Recent studies have since shown that IL-10 can also downregulate Th2 clones and their production of IL-4 and IL-5. Because of its immuno-suppressive properties, IL-10 has been suggested as a potential therapy for allergic inflammation and asthma. However, the pathophysiological role of IL-10 in vivo has not been clearly elucidated. We investigated the effects of IL-10 administration on the production of IgE, cytokine and allergen-induced Th2 cytokine production as well as its effects on eosinophilic inflammation. We established GATA-3/TCR double transgenic (GATA-3/TCR-Tg) mice by crossing GATA-3 transgenic mice with ovalbumin (OVA)-specific TCR transgenic mice; these mice were then sensitized using an intraperitoneal injection of OVA adsorbed to alum and challenged with the intratracheal instillation of an allergen. When GATA-3/TCR-Tg mice sensitized with OVA and alum were injected with C57-IL-10 cells before OVA inhalation, the levels of IL-5, IL-13, and IL-4 decreased by 40-85% and number of eosinophils decreased by 70% (P<0.03) in the murine bronchoalveolar lavage fluid (BALF). These results suggest that IL-10 plays an important role downstream of the inflammatory cascade in the Th2 response to antigens and in the development of BALF eosinophilia and cytokine production in a murine model of asthma. These immunosuppressive properties in animal models indicate that IL-10 could be a potential clinical therapy for the treatment of allergic inflammation.
    Immunobiology 12/2010; 216(7):811-20. DOI:10.1016/j.imbio.2010.12.003 · 3.04 Impact Factor
  • Source

Show more