gamma delta T Cells Promote a Th1 Response during Coxsackievirus B3 Infection In Vivo: Role of Fas and Fas Ligand

Fas/Fas ligand (FasL) interactions regulate disease outcome in coxsackievirus B3 (CVB3)-induced myocarditis. MRL super(+/+) mice infected with CVB3 develop severe myocarditis, a dominant CD4 super(+) Th1 (gamma interferon [IFN- gamma super(+)]) response to the virus, and a predominance of gamma delta T cells in the myocardial infiltrates. MRL lpr/lpr and MRL gld/gld mice, which lack normal expression of Fas and express a mutated FasL, respectively, have minimal myocarditis and show a dominant CD4 super(+) Th2 (interleukin-4 [IL-4 super(+)]) phenotype to CVB3. Spleen cells from virus-infected wild-type, lpr, and gld animals proliferate equally to virus in vitro. Adoptive transfer of gamma delta T cells from hearts of CVB3-infected MRL super(+/+) mice (FasL super(+)) into infected MRL gld/gld recipients (FasL super(-)/Fas super(+)) restores both disease susceptibility and Th1 cell phenotype. However, transfer of these cells into MRL lpr/lpr recipients (FasL super(+)/Fas super(-)) did not promote myocarditis and the viral response remained Th2 biased. This paralleled the expression of very high surface levels of FasL by myocardial gamma delta T cells, as well as their propensity to selectively lyse Th2 virus-specific CD4 super(+) T cells. These results demonstrate that Fas/FasL interactions conferred by gamma delta T cells on lymphocyte subpopulations may regulate the cytokine response to CVB3 infection and pathogenicity.