Coxsackievirus B3 (CVB3) infections cause severe myocarditis. Cardiac injury depends upon preferential activation of virus-specific CD4+ Th1 (IFNgamma+) T cell responses whereas infections resulting in CD4+ Th2 (IL-4+) cell responses cause myocarditis resistance. Early activation of T cells expressing the gamma-delta T cell receptor is pivotal in biasing CD4+ cell responses toward the Th1 phenotype. Both FasL and IFNgamma expression by the gamma-delta+ T cells are necessary for modulating CD4+ T cell responses, but the precise mechanism by which gamma-delta+ T cells regulate CD4+ adaptive immunity is not known. Gamma-delta+ T cells selectively kill virus-specific CD4+ Th2 cell clones in vitro whereas CD4+ Th1 clones are resistant. This may represent a novel mechanism for enforcing the Th1 phenotype in the heart. That CD4+ Th2 cell should be more susceptible to apoptosis than CD4+ Th1 cells is surprising. However, under certain activation conditions, Th2 cells can induce excessive cleavage of c-FLIPL, an anti-apoptotic factor, to the p43FLIP form, which is incapable of inhibiting Fas-dependent apoptosis. The delta-gamma+ T cells infiltrating the heart express high levels of FasL. The FasL(hi) phenotype may be important in myocarditis in two ways. It promotes Fas-dependent killing of the CD4+ Th2 cells and may aid gamma-delta+ T cell migration into the myocardium. The Specific Aims of this proposal are to: 1) Determine the kinetics of gamma-delta+ and CD4+ Th cell infiltration into the myocardium after H3 and H310A1 virus infections, the role of FasL in gamma-delta+ cell migration to the heart, and the relative importance of IFNgamma and FasL expression in gamma-delta+ cells in biasing the Th1 response; 2)Determine whether activation of NFAT by virus binding to gamma-delta+ and CD4+ cells is required for induction of FasL; and 3) Determine whether caspase-8 activity and cleavage of c-FLIPL is increased in CVB3-specific Th2 cells more than Th1 cells, and whether this renders Th2 targets more susceptible to being killed by gamma-deltaT cells. Determine whether increased expression of c-FLIPL in Th2 targets renders them less susceptible to lysis by gamma-delta T cells.
NIH ExPorter
NIH ExPorter