Death receptor 3 (TNFR-SF25) delivers a late-acting costimulatory signal for Th2 cytokine production during the development of allergic asthma
Date of Award
Doctor of Philosophy (Ph.D.)
Microbiology and Immunology
First Committee Member
Eckhard R. Podack, Committee Chair
Death receptor 3 (DR3) is a member of the TNF receptor superfamily with a typical death domain. The cognate ligand for DR3 has recently been identified as TL1A. Murine DR3 is constitutively expressed on NKT cells at high levels and on naive CD4 T cells at low to medium levels. In order to gain insight into the biological functions of DR3, we generated DR3-Delta5,6 and DR3-FL transgenic mice under the control of the hCD2 promoter and locus control region. CD4 T cells from these transgenic mice secreted large quantities of Th2 cytokines during the primary response. Since allergic asthma is an inflammatory disease mediated by Th2 cytokines, DR3-tg mice were compared with wt mice in their susceptibility to asthma in a classic ovalbumin model. Overexpression of DR3 in transgenes dramatically exaggerated the airway inflammation associated with asthma measured by histopathology and analysis of bronchioalveolar lavage.To determine whether blockade of DR3 ameliorated susceptibility to asthma, we generated a dominant negative mutant of DR3 transgene (DR3-DN) expressed under the same CD2 cassette. DR3-DN transgenic mice were resistant to the induction of allergic airway inflammation. In addition, during the secondary response, blocking DR3 signals in DN-tg remarkably inhibited the production of Th2 cytokines by CD4 T cells in vitro and ex vivo. These data suggested that DR3-mediated signals may act later rather than earlier in an immune response.To further test this hypothesis, we developed an antagonistic antibody to mTL1A. Treatment of OVA sensitized B6 wt mice with this antagonistic antibody during the ovalbumin airway challenge abolished the pulmonary inflammation and mucus production. In addition, we observed that a small population of CD11c+ DCs express mTL1A in the pulmonary draining lymph node cells from OVA sensitized and challenged B6 wt mice.Our data suggest that TL1A and DR3 interactions during the secondary antigen exposure in the airway trigger CD4 T cells, and probably NKT cells, to produce Th2 cytokines that mediate the allergic airway inflammation. Our data also indicate that blockade of DR3 signaling may be an effective way to treat asthma.
Health Sciences, Immunology
Fang, Lei, "Death receptor 3 (TNFR-SF25) delivers a late-acting costimulatory signal for Th2 cytokine production during the development of allergic asthma" (2004). Dissertations from ProQuest. 2131.