Thymic MHC class I gene regulation of susceptibility to lymphocytic choriomeningitis

Susceptibility of mice to intracerebral (i.c.) infection with lymphocytic choriomeningitis virus (LCMV) depends on the LCMV isolate and host genes. We have previously shown that major histocompatibility complex (MHC) class I genes regulate susceptibility to lethal disease due to infection with the LCMV-docile isolate derived from the LCMV-UBC strain. The Dq allele conferred dominant susceptibility whereas other H-2D region alleles tested (Dd, Dk, Db and Ds) conferred resistance. Susceptibility linked to Dq correlated strongly with early and potent LCMV-specific cytotoxic T cell (CTL) activation responsible for the CTL mediated immunopathological disease. To assess the extent to which thymic MHC products control lethal LCM, two studies were performed. First, (H-2Dk x H-2Dq)F1 bone marrow stem cells were used to reconstitute lethally irradiated recipients of each parental type. Reconstituted H-2Dk hosts were found to be resistant whereas H-2Dq hosts were susceptible to lethal LCM after i.c. infection, indicating that the phenotype of disease susceptibility was determined by the host. Second, we investigated the role of the thymus in the determination of resistance or susceptibility to LCM. Previously thymectomized (H-2Dk x H-2Dq)F1 mice received a thymus graft from either H-2Dk or H-2Dq fetal mice. After differentiation of F1 lymphoid precursor cells in the implanted thymus, susceptibility to lethal LCM was assessed. F1 recipient mice carrying a thymus expressing Dk were resistant whereas those carrying a thymus expressing Dq were susceptible. Therefore, as an extension of various previous studies on T cell immune responses, our results document directly that disease susceptibility to lethal LCM is controlled by MHC class I molecules of the thymus.