The systemic activation of CD8+ T cells by soluble peptide antigen results in the deletion of these cells from lymphoid organs, accompanied by their accumulation and apoptosis in the liver. Our previous studies show that presentation of antigen by non-hematopoietic cells promotes CD8+ T cell accumulation in the liver, while antigen presentation only on bone marrow-derived cells promotes increased apoptosis among liver lymphocytes. However, these experiments did not distinguish the role of intrahepatic versus systemic cells in either the bone marrow-derived or the non-hematopoietic category. Experiments using transgenic mice that express a restriction element exclusively inside or outside the liver may be difficult to interpret, due to unpredictable ectopic expression of such transgenes. The optimum experimental method is liver transplantation, but the microsurgery to perform this operation in mice is extremely challenging. An experimental micro-surgeon will join my laboratory for 2 years, starting late in 2002, and this provides a unique opportunity to extend our studies by using liver transplantation to clarify the role of antigen presentation in the intrahepatic accumulation and death of CD8+ T cells. The purpose of this RO3 application is to support construction of an optimized operating workstation, and to provide research costs for these specific experiments.
| Klein, Ingo; Cornejo, Judith C; Polakos, Noelle K et al. (2007) Kupffer cell heterogeneity: functional properties of bone marrow derived and sessile hepatic macrophages. Blood 110:4077-85 |
| Klein, Ingo; Gassel, Heinz-Jochen; Thiede, Arnulf et al. (2007) A microsurgical approach to hepatic and extrahepatic antigen presentation and its effects on the migration pattern of activated CD8(+) T cells. Microsurgery 27:289-94 |
| Klein, Ingo; Crispe, Ian Nicholas (2006) Complete differentiation of CD8+ T cells activated locally within the transplanted liver. J Exp Med 203:437-47 |
| Crispe, Ian N; Giannandrea, Matthew; Klein, Ingo et al. (2006) Cellular and molecular mechanisms of liver tolerance. Immunol Rev 213:101-18 |
