benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone and Myocarditis

Coxsackievirus B3 (CVB3) induces myocarditis, an inflammation of the myocardium, in C57Bl/6 male mice but not in mice lacking γδ+ T cells [γδ knockout (γδKO)]. Suppression of myocarditis in γδKO mice corresponds to an increase in CD4(+) CD25(+) FoxP3(+) T regulatory cells. A subpopulation of the T regulatory cells in infected γδKO mice expressed high levels of CD1d, a non-classical major histocompatibility complex class 1-like molecule. Adoptive transfer of CD1d(+) and CD1d(-) CD4(+) CD25(+) cells into infected C57Bl/6 recipients showed that the CD1d(+) subpopulation is substantially more suppressive than the CD1d(-) subpopulation. T cells expressing the γδ T-cell receptor comprised approximately 30-50% of the infiltrating lymphoid cells in the hearts of myocarditic C57Bl/6 mice and approximately half of the γδ+ cells expressed the Vγ4 T-cell receptor. The Vγ4+ cells lysed T regulatory cells from γδKO mice but not from wild-type (C57Bl/6) animals. Lysis was inhibited by antibody to CD1d and zVAD-fmk, a pan-caspase inhibitor. The Vγ4-γδ+ cells were not lytic to T regulatory cells and did not promote myocarditis. These results demonstrate that Vγ4+ cells selectively abrogate T regulatory cells through recognition of CD1d expressed on the regulatory cells and caspase-dependent apoptosis.

Topics: Adoptive Transfer; Amino Acid Chloromethyl Ketones; Animals; Antibodies, Monoclonal; Antigens, CD1d; Apoptosis; Cell Count; Coxsackievirus Infections; Cysteine Proteinase Inhibitors; Forkhead Transcription Factors; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Myocarditis; Receptors, Antigen, T-Cell, gamma-delta; Spleen; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Th1 Cells