Dr. David Lo proposes to examine the differentiation pathways of antigen presenting cells (APC), in particular dendritic cells (DC) in vivo, and the consequences of the deficiencies in the normal development of APC. This application is based on the principal investigator's recent observations in relB KO mice indicating that the relB subunit of the NF-kB complex is required for the development of thymic medulla and dendritic cells (Nature, in press). This is especially interesting, coupled with the investigator's previous observation that CD4 cells from TCR transgenic mice transferred into NOD mice (spontaneously resulting in autoimmune diabetes) induces differentiation of the DC network, and these cells are involved in a preferential stimulation of the pathogenic Th1 cell type. The principal investigator proposes three specific aims. In Specific Aim 1, the principal investigator proposes to examine whether relB expression is sufficient to trigger DC differentiation from precursors. As experimental approaches, relB expression during DC differentiation in vitro and in vivo will be monitored, along with other differentiation markers for APCs. Also, the possibility that Langerhans cells are the immediate precursors to lymph node DC will be examined and correlated with the presence of molecules involved in costimulation. Furthermore, the differentiation pathway will be investigated using the relB KO mice reconstituted with various TCR and MHC transgenic mice, as well as the relB-lacZ transgenic mice which will be generated in order to follow the cell lineage by the expression of lacZ activity. In Specific Aim 2, Dr. Lo plans to investigate the potential specialization of APC for CD4 effector cell development. Using various radiation chimeras of combinations of TCR and MHC transgenics and relB KO mice, selective DC deficiencies will be introduced and the resulting T-cell types/functions will be examined. Specific Aim 3 proposes to study the development of relB expressing thymic medullary epithelial cells from precursors in fetal and adult thymus, and the consequences of the specific presence of UEA-1+ MEC.

R01AI038375

1995-08-01

2000-07-31