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

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Abstract
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.