COOPERATION BETWEEN CYTOTOXIC AND HELPER T LYMPHOCYTES IN PROTECTION AGAINST LETHAL SENDAI VIRUS INFECTION Protection by T cells is MHC-restricted and MHC-regulated ; a model for MHC-Disease associations

The hallmark of T lymphocyte recognition is combined specificity for self MHC molecules and nominal antigen, i.e ., MHC-restricted recognition. As a rule, cytotoxic T lymphocytes (Tc)' are restricted by class I MHC molecules (K, D, and L molecules in the mouse) (1, 2), whereas T helper lymphocyte (Th) recognition is restricted by class II MHC molecules (I-A and I-E molecules in the mouse) (3, 4) . Both class I and class II molecules serve as immune response gene products regulating the magnitude of T cell responses (3-13) . Immune regulation by MHC molecules might be an important mechanism to explain MHC-disease associations, although solid evidence for this, especially in HLA-disease associations, is meager . The opportunity to study the in vivo importance of class I MHC regulation of the Tc response to a natural pathogenic agent of high virulence came with our previous demonstration (14) of a major difference in the capacity to generate a Sendai virus-specific Tc response between C57BL/6 (B6; H-2b) mice and H-2Kb mutant B6.C-H-2 b"' I (bml) mice . These mice differ from each other only in three amino acids in the H-2Kb molecule (15, 16) . B6 mice are responders to Sendai virus measured by the generation of virus-specific Tc, virus-specific Th proliferation, and NK cell activity in vitro, and by antiviral antibody production and virus-specific delayed type hypersensitivity (DTH) in vivo (14, 17, and this study) . In contrast, bm l mice are Tc nonresponders against this virus, but do not differ in any of the other immune parameters (14, 17, and this study) . These immune parameters were also studied in thymus deficient nu/nu mice . These mice show not only deficient Tc responses, but also deficient Th responses and