ABSTRACT
One mechanism regulating the ability of different subsets of T helper (Th) cells to respond to cytokines is the differential expression of cytokine receptors. For example, Th2 cells express both chains of the interferon gamma receptor (IFN-gammaR), whereas Th1 cells do not express the second chain of the IFN-gammaR (IFN-gammaR2) and are therefore unresponsive to IFN-gamma. To determine whether the regulation of IFN-gammaR2 expression, and therefore IFN-gamma responsiveness, is important for the differentiation of naive CD4(+) T cells into Th1 cells or for Th1 effector function, we generated mice in which transgenic (TG) expression of IFN-gammaR2 is controlled by the CD2 promoter and enhancer. CD4(+) T cells from IFN-gammaR2 TG mice exhibit impaired Th1 polarization potential in vitro. TG mice also display several defects in Th1-dependent immunity in vivo, including attenuated delayed-type hypersensitivity responses and decreased antigen-specific IFN-gamma production. In addition, TG mice mount impaired Th1 responses against Leishmania major, as manifested by increased parasitemia and more severe lesions than their wild-type littermates. Together, these data suggest that the sustained expression of IFN-gammaR2 inhibits Th1 differentiation and function. Therefore, the acquisition of an IFN-gamma-unresponsive phenotype in Th1 cells plays a crucial role in the development and function of these cells.
Subject(s)
Interferon-gamma/immunology , Signal Transduction/immunology , Th1 Cells/immunology , Animals , Antigens/immunology , Cell Division , Cell Polarity , Cells, Cultured , Female , Gene Expression , Hemocyanins/immunology , Humans , Immunologic Memory/immunology , Listeria monocytogenes/immunology , Listeriosis/immunology , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Mice, Transgenic , Receptors, Interferon/genetics , Receptors, Interferon/immunology , Th1 Cells/cytology , Interferon gamma ReceptorABSTRACT
The BCL-6 proto-oncogene encodes a POZ/zinc-finger transcription factor that is expressed in B cells and a subset of CD4(+) T cells within germinal centers. Recent evidence suggests that BCL-6 can act as a sequence-specific repressor of transcription, but the target genes for this activity have not yet been identified. The binding site for BCL-6 shares striking homology to the sites that are the target sequence for the interleukin-4 (IL-4)-induced Stat6 (signal transducers and activators of transcription) signaling molecule. Electrophoretic mobility shift assays demonstrate that BCL-6 can bind, with different affinities, to several DNA elements recognized by Stat6. Expression of BCL-6 can repress the IL-4-dependent induction of immunoglobulin (Ig) germ line epsilon transcripts, but does not repress the IL-4 induction of CD23 transcripts. Consistent with the role of BCL-6 in modulating transcription from the germ line epsilon promoter, BCL-6(-/-) mice display an increased ability to class switch to IgE in response to IL-4 in vitro. These animals also exhibit a multiorgan inflammatory disease characterized by the presence of a large number of IgE(+) B cells. The apparent dysregulation of IgE production is abolished in BCL-6(-/-) Stat6(-/-) mice, indicating that BCL-6 regulation of Ig class switching is dependent upon Stat6 signaling. Thus, BCL-6 can modulate the transcription of selective Stat6-dependent IL-4 responses, including IgE class switching in B cells.
Subject(s)
DNA-Binding Proteins/metabolism , Immunoglobulin Class Switching , Immunoglobulin E/genetics , Interleukin-4/pharmacology , Proto-Oncogene Proteins/metabolism , Trans-Activators/metabolism , Transcription Factors/metabolism , Animals , B-Lymphocytes/immunology , Binding Sites , Gene Expression Regulation , Germ Cells/metabolism , Mice , Mice, Knockout , Protein Binding , Proto-Oncogene Proteins c-bcl-6 , STAT6 Transcription Factor , Signal Transduction , Trans-Activators/genetics , Transcription, GeneticABSTRACT
To study the role of the interferon- (IFN) gammaR2 chain in IFN-gamma signaling and immune function, IFN-gammaR2-deficient mice have been generated and characterized. Cells derived from IFN-gammaR2 -/- mice are unable to activate either JAK/STAT signaling proteins or gene transcription in response to IFN-gamma. The lack of IFN-gamma responsiveness alters IFN-gamma-induced Ig class switching by B cells from these mice. In vitro cultures of T cells demonstrate that the T cells from the IFN-gammaR2 -/- mice have a defect in Th1 cell differentiation. The IFN-gammaR2 (-/-) mice also produce lower amounts of IFN-gamma in response to antigenic challenge. In addition, IFN-gammaR2 -/- mice are defective in contact hypersensitivity and are highly susceptible to infection by Listeria monocytogenes. These results demonstrate that the IFN-gammaR2 is essential for IFN-gamma-mediated immune responses in vivo.
