Consequences of a single Ir-gene defect for the pathogenesis of lymphocytic choriomeningitis

The H-2L^d allele has been identified by others as the sole Ir gene in the H-2^d haplotype for the cytotoxic T lymphocyte (CTL) response to mouse lymphocytic choriomeningitis virus (LCMV). The BALB/c-H-2^dm2 (C-H-2^dm2) mutant lacks H-2L^d, and thus should be ideal for assessing the contribution of virus-immune CTL to LCM immunopathology. Comparison of the C-H-2 dm2 mice with congenic BALB/c mice revealed that there is a delay of about 24 h in the onset of severe inflammatory process and symptoms in the mutant strain, but the absence of H-2L^d did not prevent the later development of fatal disease in mice injected intracerebrally (i.e.) with neurotropic LCMV. This could indicate that virus-immune CTL are not the major mediators of clinical LCM. Spleen cells from LCMV-primed BALB/c mice did not show CTL activity for LCMV-infected C3H.OH, C-H-2^dm2, or (CBA × C-H-2^dm2)F₁ target cells. However, immune lymphocytes from both the mutant and the F₁ strains lyse virus-infected BALB/c cells. Furthermore, BtO.HTG and, in some experiments, B10.A(5R) mice generated CTL lytic for LCMV-infected BALB/c, C-H-2^dm2, and (CBA × CH-2^dm2)F₁ macrophages. Apparently H-2L^d is immunodominant in the H-2^d restricted response to LCMV. However, in the absence of H-2L^d, it seems that H-2K^d and, to a lesser extent, H-2D^d also serve as Ir genes for the CTL response in this infection. Even so, the absence of the H-2L^d-restricting element results in a disease process which is either delayed in onset or less severe.