The experiments proposed in this application are designed to address the role of specific T cell accessory molecule interactions in the generation of a pulmonary inflammatory response. It has been shown in animal models of inflammatory lung disease that the T lymphocyte is critical in the recruitment of leukocytes and the initiation of the inflammatory cascade. However, interruption of effector cytokines has had only marginal success in the prevention of the development of pulmonary inflammatory diseases. Manipulation of the signals required to initiate T cell function may be a more promising approach. The initiation of T cell proliferation and effector function requires not only antigen receptor signaling, but the interaction of other receptor ligand pairs. These additional signals have been termed costimulatory signals. CD28 has been demonstrated to be a bona fide costimulatory interaction in both in vitro and in vivo studies. Preliminary studies investigating the T cell function of CD28-deficient mice has led to the identification of CD43 as a potential important mediator of both T cell activation and cell death.
The specific aims are l) Determine the basis for the differential induction of proliferation or cell death following CD43 ligation. 2) Determine if the absence of CD43 signaling alters the outcome of an immune response in vitro, and 3) Examine the role of T cell costimulatory molecules CD43 and CD28 in the generation of a pulmonary inflammatory response. Specific inhibitors of these interactions and transgenic animals will allow for the careful evaluation of the contribution of these costimulatory interactions in the development of inflammatory lung disease. These studies have the potential for leading to new,specific treatments for immune mediated pulmonary disease. The work described above will be complemented by didactic training in several formats. Washington University has an extensive seminar series in both immunology and pulmonary medicine in which Dr. Green will be an active participant. Enrollment in formal course work on advanced topics of immunology and molecular biology will further enhance the training received under this award. The availability of internationally recognized researchers in both immunology and pulmonary medicine provide an ideal environment for the accomplishment of the research goals proposed in this application.
| Green, J M; Karpitskiy, V; Kimzey, S L et al. (2000) Coordinate regulation of T cell activation by CD2 and CD28. J Immunol 164:3591-5 |
| Walker, J; Green, J M (1999) Structural requirements for CD43 function. J Immunol 162:4109-14 |
| Holdorf, A D; Green, J M; Levin, S D et al. (1999) Proline residues in CD28 and the Src homology (SH)3 domain of Lck are required for T cell costimulation. J Exp Med 190:375-84 |
| Thurman, E C; Walker, J; Jayaraman, S et al. (1998) Regulation of in vitro and in vivo T cell activation by CD43. Int Immunol 10:691-701 |
