The biological function of death receptor 3 (DR3, TNFR-SF12) is not well characterized. We have discovered recently that DR3 is a critical receptor in the induction of inflammatory lung disease in the murine ovalbumin asthma model. In the murine ovalbumin asthma model DR3 transgenic mice have exaggerated lung inflammation when compared to non transgenic litter mates. In contrast, mice expressing the dominant negative form of DR3 have no lung inflammation, the DR-DN transgene apparently suppresses the lung inflammation normally seen in w.t. mice. To validate this observation we have generated a blocking antibody binding to and blocking TL1A (TNF-SF15), the ligand normally engaging DR3. Antagonistic anti TL1A given during airway ovalbumin challenge to normal ovalbumin primed mice completely blocked the inflammatory lung response seen without antibody or with control antibody. Since newborn mice and children exhibit a striking Th2 bias that upon normal development of the immune system transitions to a Th1 bias in adults, we determined whether new born mice expressed higher levels of DR3 on their T cells than adult mice. This was indeed the case suggesting that DR3 expression is correlated with the Th2 bias of developing mice. We also found that DR3 expression, unlike that of any other member of the TNF-R family, is controlled by alternative mRNA splicing. Resting T cells express no or little DR3 protein but contain high levels of randomly spliced DR3 mRNA. Upon T cell activation via the T cell receptor, protein kinase C (PKC) is activated and mediates correct splicing of full length DR3 and surface expression of the protein. This unique regulation of DR3 expression allows for rapid DR3 protein expression on T cells. In addition it enables environmental regulation of DR3 expression via influencing PKC levels responsible for DR3 splicing and expression. Based on these data we will test the following hypotheses: Hypothesis 1: DR3 signals are major contributors to induction of acute inflammatory lung disease and asthma; DR3 is a critical component of asthma pathogenesis. Hypothesis 2: Neonatal and young mice exhibit a Th2 bias upon T cell activation and express increased levels of DR3 on resting and activated T cells. DR3 expression is causally related to the TH2 bias during development. Hypothesis 3: DR3 expression on resting and activated lymphocytes is controlled by alternative splicing of preformed mRNA; splicing in turn is controlled by protein kinase C. Environmental (infectious) influences can alter DR3 expression via altering of splicing. Hypothesis 4: Atopic asthmatic children exhibit a TH2 bias and express DR3. This will be validated in a Clinical Study.