The long term goal of these investigations is to further our understanding of the molecular mechanisms involved in recognition of foreign antigens during antigen specific cellular cytotoxicity. Cellular cytotoxicity is important for the protection of the host from viral and neoplastic disease, and in some cases mediates immune injury. T lymphocytes bearing the CD8+ marker mediate antigen specific cellular cytotoxicity in the normal host and use the class I major histocompatibility complex (MHC) molecule for recognition of viral antigen. Mice deficient in beta2-microglobulin (beta2m-/-) are deficient in cell surface class I MHC molecules, and therefore are deficient in CD8+ cytotoxic T lymphocytes (CTL). We have found that in beta2m-/- mice CD4+ CTL mediate antigen specific cellular cytotoxicity toward lymphocytic choriomeningitis virus (LCMV), and these CTL use class II MHC molecules for recognition of viral antigen. CD4+ CTL are found in normal animals during infections with both viruses and bacteria but are of uncertain significance in protection or immune injury. We propose to use beta2m-/- mice, deficient in class I MHC molecules and CD8+ CTL, to study the function of CD4+ CTL on the whole animal level, in tissue culture, and on the molecular level. We will address the following hypotheses: 1. In beta2m-/- mice CD4+ CTL can take over most of the functions of CD8+ CTL, both in protection of the host from viral infection as well as in the mediation of immune injury. 2. CD4+ CTL have important roles in the immune response in normal animals and humans. 3. CD8+ CTL predominate over CD4+ CTL in normal mice based on the molecular aspects of antigen processing and cellular interactions. We will use LCMV as the viral model because of the dependence on CD8+ CTL for the major immune response in normal animals. We also propose beginning studies with herpes simplex virus, since normal animals generate CD4+ CTL in the immune response. We will compare the CD4+ CTL response in class I MHC deficient mice with the predominant CD8+ CTL response in mice that have class I MHC, this will allow us to identify mechanisms at work in normal mice limiting the predominance of CD4+ CTL in most infections. These studies are relevant to viral infection s in man as CD4+ CTL are founding during infection with mycobacteria, influenza, measles, herpes simplex, hepatitis B, and the human immunodeficiency virus and CD4+ CTL may have a role in immune injury in these infections.
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