Slam Haplotype 2 Promotes NKT But Suppresses Vγ4+ T-Cell Activation in Coxsackievirus B3 Infection Leading to Increased Liver Damage But Reduced Myocarditis

There are two major haplotypes of signal lymphocytic activation molecule (Slam) in inbred mouse strains, with the Slam haplotype 1 expressed in C57Bl/6 mice and the Slam haplotype 2 expressed in most other commonly used inbred strains, including 129 mice. Because signaling through Slam family receptors can affect innate immunity [natural killer T cell (NKT) and gamma-delta T-cell receptor], and innate immunity can determine susceptibility to coxsackievirus 83 (CVB3) infection, the present study evaluated the response of C57Bl/6 and congenic B6.129c1 mice (expressing the 129-derived Slam locus) to CVB3. CVB3-infected C57Bl/6 male mice developed increased myocarditis but reduced hepatic injury compared with infected B6.129c1 mice. C57Bl/6 mice also had increased gamma delta(+) and CD8(+)interferon-gamma(+) cells but decreased numbers of NKT (T-cell receptor beta chain + mCD1d tetramer(+)) and CD4(+)FoxP3(+) cells compared with B6.129c1 mice. C57BV6 mice were infected with CVB3 and treated with either alpha-galactosylceramide, an NKT cell-specific Ligand, or vehicle (dimethyl sulfoxide/PBS). Mice treated with alpha-galactosylceramide showed significantly reduced myocarditis. Liver injuries, as determined by alanine aminotransferase levels in plasma, were increased significantly, confirming that NKT cells are protective for myocarditis but pathogenic in the liver. (Am J Pathol 2013, 182: 401-409; http://dx.doi.org/10.1016/j.ajpath.2012.10.019)