The goal of this project is to understand the mechanisms that lead to CD4 T cell activation in the absence of conventional CD28 costimulation. T cells that express a functional receptor tyrosine kinase (fibroblast growth receptor-1, FGFR-1) are increased in chronic inflammation associated with cardiac allograft rejection and rheumatoid arthritis. Engagement of the T cell receptor plus fibroblast growth factor - 1 (FGF-1) costimulation results in increased IL-2 production, and induction of AP-1 and NF-kB transcription elements. In the first aim, shared pathways in CD28 and FGFR-1 mediated T cell activation will be elucidated through studies of NF-kB induction. These studies will utilize electrophoretic mobility shift assays and supershifts to determine unique Rel/NF-kB members induced by FGFR-1. Furthermore, novel Jurkat T cells with non-functional NF-kB pathways will be utilized to directly demonstrate the requirement of NF-kB induction for FGF- mediated T cell activation. In the second major aim, the role of FGF-1 signaling in T cell differentiation and effector function will be determined by examining the relationship of FGFR-1 stimulation with differentiation into TH1 or TH2 subsets. These studies will be extended by using mice transgenic for reporter genes driven by IL-4 and IFN-Y promoter elements to determine how FGF-1 regulates TH1/TH2 activation or repression. The third major aim will characterize the role of FGFR-1 action in T cell development and disease using transgenic mice with a non-signaling, dominant negative FGFR-1 targeted to the thymus and peripheral T cells. This transgenic model will be applicable to future investigations of FGF-1 responsive T cells in a variety of disorders, including inflammatory arthritis, tumor biology, and allograft rejection. The availability of these transgenic animals will provide a resource for this Mentored Clinical Scientist Development Award to evolve into an independent project.
|Byrd, Victor M; Kilkenny, Dawn M; Dikov, Michael M et al. (2003) Fibroblast growth factor receptor-1 interacts with the T-cell receptor signalling pathway. Immunol Cell Biol 81:440-50|
|Thomas, J W; Thieu, T H; Byrd, V M et al. (2000) Acidic fibroblast growth factor in synovial cells. Arthritis Rheum 43:2152-9|
|Byrd, V M; Ballard, D W; Miller, G G et al. (1999) Fibroblast growth factor-1 (FGF-1) enhances IL-2 production and nuclear translocation of NF-kappaB in FGF receptor-bearing Jurkat T cells. J Immunol 162:5853-9|