THE CD8(+) T-CELL REPERTOIRE IN BETA(2)-MICROGLOBULIN-DEFICIENT MICE IS BIASED TOWARDS REACTIVITY AGAINST SELF-MAJOR HISTOCOMPATIBILITY CLASS-I

beta(2)-Microglobulin-deficient (beta(2)m -/-) mice are reported to lack cell surface expression of major histocompatibility complex (MHC) class I molecules, CD8(+) T cells, and the ability to mount MHC class I-specific T cell responses. We have observed that beta(2)m -/- mice possess CD8(+) T cells that can be induced to perform strong allospecific cytotoxic responses against nonself-MHC class I by in vivo priming. We report that these beta(2)m -/- cytotoxic T lymphocyte (CTL) differ from those induced in beta(2)m-positive littermates in that they cross-react and kill cells expressing self-MHC class I at normal ligand density with beta(2)m. beta(2)m -/- CTL could even be induced in primary mixed lymphocyte culture by self-MHC class I expressing stimulator cells, whereas allogeneic stimulator cells failed to elicit a response under similar conditions. Cells with a reduced cell surface MHC class I expression were less sensitive, while syngeneic beta(2)m -/- cells were resistant to the beta(2)m -/- CTL. This antiself-MHC reactivity could not be induced when beta(2)m -/- T cells matured in an environment with normal MHC class I expression in bone marrow chimeric mice. Antiself-MHC reactivity was also observed against human peptide loading-deficient cells expressing the appropriate murine class I molecules, suggesting that affinity to self-MHC class I may occur irrespective of peptide content. The results fit with a model where positive and negative selection of CD8(+) T cells in beta(2)m -/- mice is mediated by low levels of MHC class I free heavy chains. In this model, low ligand density on selecting cells leads to positive selection of rare T cells that bind to low levels of MHC class I free heavy chains, resulting in a very small peripheral CD8(+) compartment. Due to low density of the selecting ligand, negative selection does not remove T cells recognizing beta(2)m-positive cells expressing self-MHC class I at normal ligand density, which generates a T cell repertoire that would be autoreactive in a beta(2)m-positive littermate. The first ''MHC deficient'' animals thus paradoxically provide a tool for direct demonstration and analysis of self MHC bias in the T cell repertoire.