T and B cell tolerance and responses to viral antigens in transgenic mice: implications for the pathogenesis of autoimmune versus immunopathological disease.
Experiments with transgenic mice illustrate clonal elimination of T cells specific for antigens expressed appropriately in the thymus, but presence of inducible T cells when the antigen presented on class I MHC antigens is expressed exclusively on non-lymphohemopoietic cells in the periphery (pancreatic beta islet cells). TCR-transgenic LCMV-carrier mice expressing LCMV in the thymus exhibit clonal elimination at the early CD4+8+ thymocyte stage, causing CTL unresponsiveness in these mice. In contrast, studies with RIP LCMV-GP-transgenic mice (expressing GP in pancreatic beta cells) and with TCR-RIP LCMV-GP double-transgenic mice show that CTL reactivity is normal. These experiments argue against so-called peripheral anergy of class I MHC antigen-restricted cytotoxic T cells as a general mechanism of peripheral immunological tolerance to self. They reveal that self epitopes that are genetically self and presented by class I antigens may not be considered immunologically self if expressed solely extrathymically, despite the fact that they are antigenic and can be recognized by induced effector T cells. Genetic self that is presented on cells which can induce neither tolerance nor an immune response is immunologically dealt with as foreign and therefore may be called nonimmunological self. Appropriate presentation of the same epitope on antigen-presenting cells promptly induces effector T cells and causes disease; such disease should not be called autoimmune because it is an immunopathological T-cell mediated disease, comparable to an unfavorably balanced immunopathological T-cell response to a virus. Mechanisms that control autoantibody responses were studied in mice expressing a viral transgene. Such mice generate neutralizing antiviral autoantibody responses only when the transgenic viral antigen is linked to a foreign T-helper determinant. These findings, therefore, document differences in levels of T- vs B-cell tolerance (so-called split tolerance) under a given expression level of a "self" antigen. They illustrate how unresponsiveness of B cells to produce T-independent IgM is dose-dependent and that IgG autoantibodies are triggered by introducing foreign T-helper determinants that can be recognised in a linked fashion. This model suggests that, while T-cell tolerance to tolerogenic self in the thymus is solid, B-cell tolerance in general is not. From the point of view of autoantibody responses these T-helper cells may also be called immunopathological; i.e., these T-helper cells are specific for foreign epitopes that, via linked recognition, trigger truly autoimmune B cells.(ABSTRACT TRUNCATED AT 400 WORDS)