Vγ4(+) T Cells Promote Autoimmune CD8(+) Cytolytic T-Lymphocyte Activation in Coxsackievirus B3-Induced Myocarditis in Mice: Role for CD4(+) Th1 Cells

T cells expressing the Vγ4 T-cell receptor (TCR) promote myocarditis in coxsackievirus B3 (CVB3)-infected BALB/c mice. CD1, a major histocompatibility complex (MHC) class I-like molecule, is required for activation of Vγ4(+) cells. Once activated, Vγ4(+) cells initiate myocarditis through gamma interferon (IFN-γ)-mediated induction of CD4(+) T helper type 1 (Th1) cells in the infected animal. These CD4(+) Th1 cells are required for activation of an autoimmune CD8(+) αβ TCR(+) effector, which is the predominant pathogenic agent in this model of CVB3-induced myocarditis. Activated Vγ4(+) cells can adoptively transfer myocarditis into BALB/c mice infected with a nonmyocarditic variant of CVB3 (H310A1) but cannot transfer myocarditis into either uninfected or CD1(−/−) recipients, demonstrating the need for both infection and CD1 expression for Vγ4(+) cell function. In contrast, CD8(+) αβ TCR(+) cells transfer myocarditis into either infected CD1(−/−) or uninfected recipients, showing that once activated, the CD8(+) αβ TCR(+) effectors function independently of both virus and CD1. Vγ4(+) cells given to mice lacking CD4(+) T cells minimally activate the CD8(+) αβ TCR(+) cells. These studies show that Vγ4(+) cells determine CVB3 pathogenicity by their ability to influence both the CD4(+) and CD8(+) adaptive immune response. Vγ4(+) cells enhance CD4(+) Th1 (IFN-γ(+)) cell activation through IFN-γ- and CD1-dependent mechanisms. CD4(+) Th1 cells promote activation of the autoimmune CD8(+) αβ TCR(+) effectors.