T cells expressing the gamma delta T cell receptor (TcR) often accumulate at sites of inflammation. What role these cells play in disease processes is unclear. However, studies investigating a murine model of coxsackievirus B3 (CVB3)-induced myocarditis imply that these cells modulate CD4+ Th cell responses. Myocarditis generally correlates to the induction of Thl CD4+ cell responses while preferential activation of Th2 cells causes disease resistance. Adoptive transfer of activated gamma delta+ cells into myocarditis-resistant mice results in a shift from Th2 to Thl cell activation and a corresponding induction of myocardial inflammation. These results agree with published reports which state that gamma delta+ cells preferentially downregulate Th2 cell responses. While gamma delta+cells are both potent producers of immunoregulatory cytokines and mediators of Fas-dependent apoptosis, apoptosis may be the primary method of CD4+ cell modulation based on studies using mice expressing either the Ipr or gld mutation. In addition to its effects on CD4+ cell regulation, apoptosis may also be the basis for the induction of dilated cardiomyopathy in myocarditic animals.
The Specific Aims of the present proposal are to: 1) Characterize the gamma delta+ cell populations in the hearts of myocarditic CVB3-infected mice and determine whether all or only selected gamma delta+ cell populations modulate CD4+ Th cell responses; 2) Determine whether gamma delta+ T cells kill Th2 cells through Fas-dependent or non-Fas-dependent pathways; and 3) Evaluate whether co-stimulatory factors on Th2 cell clones promote killing or rescue Thl cells from death.
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