No abstract

Complete T-cell activation requires two distinct signals, one delivered via the T-cell receptor, and the second "co-stimulatory" signal through CD28/B7 ligation. Previous studies showed that the blockade of CD28/B7 ligation alters differentiation of Th1/Th2 lymphocyte subsets in vitro and in vivo. The present study was designed to determine the effect of a CD28/B7 antagonist (CTLA4Ig) on Th1/Th2 development in Schistosoma mansoni-sensitized and airway-challenged mice. Treatment of mice with CTLA4Ig beginning 1 wk after sensitization abolished airway responsiveness to intravenous methacholine determined 96 h following antigen challenge. We also found a significant reduction in bronchoalveolar lavage (BAL) eosinophilia, and reduced peribronchial eosinophilic infiltration and mucoid-cell hyperplasia. Furthermore, CTLA4Ig treatment significantly decreased interleukin (IL)-4 and IL-5 content in BAL fluid in vivo, and the production of IL-5 by lung lymphocytes stimulated with soluble egg antigen (SEA) in vitro. In contrast, the content of interferon-gamma in BAL fluid and supernatant from SEA-stimulated lung lymphocytes from CTLA4Ig-treated mice was increased significantly compared with untreated animals. Thus, CTLA4Ig inhibits eosinophilic airway inflammation and airway hyperresponsiveness in S. mansoni-sensitized and airway-challenged mice, most likely due to attenuated secretion of Th2-type cytokines and increased secretion of Th1-type cytokines.

TRAF4 is one of six identified members of the family of TNFR-associated factors. While the other family members have been found to play important roles in the development and maintenance of a normal immune system, the importance of TRAF4 has remained unclear. To address this issue, we have generated TRAF4-deficient mice. Despite widespread expression of TRAF4 in the developing embryo, as well as in the adult, lack of TRAF4 expression results in a localized, developmental defect of the upper respiratory tract. TRAF4-deficient mice are born with a constricted upper trachea at the site of the tracheal junction with the larynx. This narrowing of the proximal end of the trachea results in respiratory air flow abnormalities and increases rates of pulmonary inflammation. These data demonstrate that TRAF4 is required to regulate the anastomosis of the upper and lower respiratory systems during development. The tumor necrosis factor receptor (TNFR) family is a still expanding family of receptors that are involved in signal transduction pathways primarily during immune and inflammatory responses.1 Each receptor binds to a ligand from the TNF family, which results in multimerization of receptor monomers and in signaling responses ranging from proliferation and differentiation to apoptosis. The various family members have considerable homology in their extracellular domains due to the presence of cysteine-rich motifs required for ligand binding. With the exception of a certain subset of receptor family members that contain the so-called death domain (DD) motif in their cytoplasmic domain, the cytoplasmic tails of the proteins have a much more limited homology.Recently, a group of proteins that bind to the cytoplasmic tail of several TNFR family members has been identified. These proteins are named TRAFs (for TNFR-associated factors), and to date six family members have been described. All TRAFs share a ϳ150-amino acid C-terminal TRAF domain that mediates the interaction between the TRAF and its receptor(s) 2-4 or other proteins, as well as a more loosely conserved region of zinc finger repeats. A similar domain can also be found in the meprin family of mammalian zinc metalloendopeptidases.5