ABSTRACT
IL-4 is required for the pathogenesis of atopic diseases and immune regulation. Stat6 is critical for IL-4-induced gene expression and Th cell differentiation. Recently, we have generated mice expressing a mutant Stat6 (Stat6VT) under control of the CD2 locus control region that is transcriptionally active independent of IL-4 stimulation. To determine whether active Stat6 in T cells is sufficient to alter immune regulation in vivo, we mated Stat6VT transgenic mice to IL-4-deficient mice. Stat6VT expression in IL-4-deficient lymphocytes was sufficient to alter lymphocyte homeostasis and promote Th2 differentiation in vitro. HyperTh2 levels in Stat6 transgenic mice correlated with an atopic phenotype that manifested as blepharitis and pulmonary inflammation with a high level of eosinophilic infiltration. In the absence of endogenous IL-4, Stat6VT transgenic mice were protected from allergic inflammation. Thus, in mice with hyperTh2 immune responses in vivo, IL-4 is a critical effector cytokine.
Subject(s)
Cytokine Receptor gp130/genetics , Hypersensitivity/immunology , Hypersensitivity/pathology , Inflammation Mediators/physiology , Interleukin-4/physiology , STAT6 Transcription Factor/genetics , Amino Acid Substitution/genetics , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Blepharitis/genetics , Blepharitis/immunology , Blepharitis/pathology , Cell Differentiation/genetics , Cell Differentiation/immunology , Cytokine Receptor gp130/biosynthesis , Cytokine Receptor gp130/physiology , Homeostasis/genetics , Homeostasis/immunology , Hypersensitivity/genetics , Inflammation Mediators/metabolism , Interleukin-4/deficiency , Interleukin-4/genetics , Lung/immunology , Lung/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , STAT6 Transcription Factor/biosynthesis , STAT6 Transcription Factor/physiology , Th2 Cells/immunology , Th2 Cells/metabolism , Th2 Cells/pathologyABSTRACT
B-lymphocyte homeostasis and function are regulated by complementary actions of the TNFR family members TACI, BCMA, and BAFF-R, which are expressed by mature B cells. How these receptors are differentially activated is not entirely understood, because the primary ligand BAFF binds to all three. We searched for alternative ligands for TACI using recombinant TACI-Fc fusion protein as a probe and identified syndecan-2 as a new binding partner. TACI binding appears to require heparan sulfate posttranslational modifications of syndecan-2, because free heparin or pretreatment with heparitinase blocked the interaction. Syndecan-2 bound TACI but bound neither BAFF-R nor BCMA. Transfected cells expressing syndecan-2 activated signaling through TACI, as indicated by an NFAT-specific reporter. Syndecan-1 and syndecan-4 were also able to induce TACI signaling in a similar manner. This is the first identification of ligands that selectively activate TACI without simultaneously triggering BCMA or BAFF-R. This finding may help explain the alternative outcomes of signaling from this family of receptors in B cells.
