PREDICTIONS FROM THE 'DANGER' MODEL: We are studying immunity from the point of view of the 'Danger' model, a new model of the immune system that suggests that its primary function is to discriminate: between dangerous and harmless things. We have begun to test several predictions 1) Neonatal Tolerance: Female mice can be primed by male dendritic cells or tolerized by male B cells at any time of their life. This result was not predicted by the old 'self-non-self' model which proposed that tolerance to 'self' is set early in life. 2) B cell deficient mice: We predicted that B cells are not APCs for naive T cells and tested their importance in B cell deficient mice. The T cells in these animals are perfectly able to respond to protein antigens, minor H antigens and parasites. Their responses do not differ in any way from those of the T cells in B cell sufficient mice. 3) Danger signals. Using a sensitive PCR based RNA subtraction method, we are searching for danger signals in a skin sensitization model. TOLERANCE 1) Maternal tolerance Using quantitative PCR for the Y chromosomes we occasionally find male cells in the organs of pregnant mice. This traffic is very sporadic and the cells are rejected by the maternal immune system while the fetus itself is not. Therefore maternal acceptance of the fetus is most likely produced by the fetal-placental unit, rather than by fetal to maternal traffic. We predict, by the 'danger' model that contact with the healthy fetal cells should generate local tolerance in maternal lymphocytes. 2) Results of tolerance in Tg mice To test which haplotypes support the development of a Tg TCR derived from an F1 mouse, we created T cell clones from F1 mice, isolated the genes for their antigen specific receptors and generated Tg mice. Preliminary results suggest that female Tg mice carrying a receptor against the H-Y antigen have pregnancy problems. We now have four transgenic lines and are breeding them to rag KO mice in order to analyze their receptors. T CELL MEMORY: We found that killer cell memory lasts at least 9 months in the absence of T helper cells or B cells. THE THYMIC STEM CELL is it precommitted? We have found that commitment to T cell developmental occurs in the thymus, not earlier, and that the first development steps in the thymus are random, producing cell types that cannot develop there.