Vγ1+ T Cells Suppress and Vγ4+ T Cells Promote Susceptibility to Coxsackievirus B3-Induced Myocarditis in Mice

Abstract

Coxsackievirus B3 infections of C57BL/6 mice, which express the MHC class II IA but not IE Ag, results in virus replication in the heart but minimal myocarditis. In contrast, Bl.Tg.Eα mice, which are C57BL/6 mice transgenically induced to express IE Ag, develop significant myocarditis upon Coxsackievirus B3 infection. Despite this difference in inflammatory damage, cardiac virus titers are similar between C57BL/6 and Bl.Tg.Eα mice. Removing γδ T cells from either strain by genetic manipulation (γδ knockout(ko)) changes the disease phenotype. C57BL/6 γδ ko mice show increased myocarditis. In contrast, Bl.Tg.Eα γδ ko mice show decreased cardiac inflammation. Flow cytometry revealed a difference in the γδ cell subsets in the two strains, with Vγ1 dominating in C57BL/6 mice, and Vγ4 predominating Bl.Tg.Eα mice. This suggests that these two Vγ-defined subsets might have different functions. To test this possibility, we used mAb injection to deplete each subset. Mice depleted of Vγ1 cells showed enhanced myocarditis, whereas those depleted of Vγ4 cells suppressed myocarditis. Adoptively transfusing enriched Vγ4+ cells to the C57BL/6 and Bl.Tg.Eα γδ ko strains confirmed that the Vγ4 subset promoted myocarditis. Th subset analysis suggests that Vγ1+ cells biased the CD4+ T cells to a dominant Th2 cell response, whereas Vγ4+ cells biased CD4+ T cells toward a dominant Th1 cell response.

MHC class I-dependent Vγ4+pulmonary T cells regulate αβ T cell-independent airway responsiveness

“…This finding is consistent with other recent studies associating TCR-defined subsets of ␥␦ T cells with distinct functional roles (23,(25)(26)(27)(28). The requirement for a TCR-defined population also suggests that TCR-ligand recognition and the particular specific ligand of the regulatory ␥␦ T cell subset are important in maintaining normal airway function (29).…”

“…In contrast, anti-TCR-V␥1 mAb had no effect (Fig. 2 E and F), although this Ab efficiently depletes V␥1 ϩ T cells as we have demonstrated (23). These results established the V␥4 ϩ T cell subset as a negative regulator of airway responsiveness in C57BL͞6 mice.…”

Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis

“…66 Investigation of ␥␦ T cell subsets in coxsackieviral myocarditis has shown that V␥1ϩ T cells suppress myocardial inflammation whereas the V␥4ϩ subset promoted myocarditis. 67 The V␥4 subset was found to produce interferon (IFN)-␥ and promote TH1 responses.…”

γδ T cells affect IL-4 production and B-cell tolerance

“…In mice and humans, it was found that functional attributes of γδ T cells segregate with expressed γδ T-cell receptors (TCRs) (8,9), although functional differentiation has also been observed within or across TCR-defined subsets and correlated with other markers, such as CD27 and CD8 (10,11). The murine TCR-γ locus contains seven Vγ genes, six of which are functional and expressed on the cell surface (3,12).…”