γδ⁺T Cells Regulate Major Histocompatibility Complex Class II (IA and IE)-Dependent Susceptibility to Coxsackievirus B3-Induced Autoimmune Myocarditis

Abstract

Coxsackievirus B3 (CVB3) infection induces myocardial inflammation and myocyte necrosis in some, but not all, strains of mice. C57BL/6 mice, which inherently lack major histocompatibility complex (MHC) class II IE antigen, develop minimal cardiac lesions despite high levels of virus in the heart. The present experiments evaluate the relative roles of class II IA and IE expression on myocarditis susceptibility in four transgenic C57BL/6 mouse strains differing in MHC class II antigen expression. Animals lacking MHC class II IE antigen (C57BL/6 [IA+ IE−] and ABo [IA− IE−]) developed minimal cardiac lesions subsequent to infection despite high concentrations of virus in the heart. In contrast, strains expressing IE (ABo Eα [IA− IE+] and Bl.Tg.Eα [IA+ IE+]) had substantial cardiac injury. Myocarditis susceptibility correlated to a Th1 (gamma interferon-positive) cell response in the spleen, while disease resistance correlated to a preferential Th2 (interleukin-4-positive) phenotype. Vγ/Vδ analysis indicates that distinct subpopulations of γδ+ T cells are activated after CVB3 infection of C57BL/6 and Bl.Tg.Eα mice. Depletion of γδ+ T cells abrogated myocarditis susceptibility in IE+ animals and resulted in a Th1→Th2 phenotype shift. These studies indicate that the MHC class II antigen haplotype controls myocarditis susceptibility, that this control is most likely mediated through the type of γδ T cells activated during CVB3 infection, and finally that different subpopulations of γδ+ T cells may either promote or inhibit Th1 cell responses.

Immune responsiveness against allogeneic platelet transfusions is determined by the recipient's major histocompatibility complex class II phenotype

“…Furthermore, I‐E expression has been shown to alter the T‐cell repertoire through clonal selection in the thymus. For example, Huber and colleagues 29 demonstrated that the T‐cell repertoires in the spleens of C57BL/6 (I‐A+I‐E–) and 107‐1 I‐E Tg (I‐A+/I‐E+) mice differ substantially. Perhaps the way allogeneic PLT antigens are displayed on the recipient's MHC class II molecules during antigen presentation determines the outcome of the IgG isotype response against allogeneic PLT transfusions.…”

Cd45rc- γδ+ T–Cell Infiltration Is Associated With Immunologic Unresponsiveness Induced by Prior Donor–Specific Blood Transfusion in Rat Hepatic Allografts

“…15 Different subpopulations of ␥␦ ϩ T cells may either promote or inhibit Th1 cells. 46 In fact, IL-4 production by ␥␦ ϩ T cells is involved in the down-regulation of Th1 cells 47 and facilitates Th2-mediated responses. 48,49 These observations suggest the importance of ␥␦ ϩ T cells in the immune response.…”

The group B coxsackieviruses and myocarditis

“…Huber and colleagues [141] demonstrated that treatment of females with testosterone increases the CD4+ Th1 response and increases the amount of cd T cell activation. Further studies [142,143] correlated specific subsets of cd T cells with severity of CVB3-induced myocarditis. This work indicates that oestrogen and testosterone can alter the Th1/Th2 immune response perhaps through activation of cd T cells and specific cd subsets activated to differing extents in resistant and susceptible strains of mice may be critical for the extent of CVB3-induced myocarditis.…”

“…This work indicates that oestrogen and testosterone can alter the Th1/Th2 immune response perhaps through activation of cd T cells and specific cd subsets activated to differing extents in resistant and susceptible strains of mice may be critical for the extent of CVB3-induced myocarditis. The C57BL/ 6 strain (CVB3-induced myocarditis resistant) can be made susceptible by making the strain MHC class II IE + [142,143]. The C57BL/6 mice have increased amounts of cd T cells of the Vc1 subset and greater amounts of Th2 type CD4+ T cell.…”