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

Abstract

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.