Colitis can be induced in immune deficient (SCID or RAG -/-) mice by the transfer of CD4+ CD45RB/high T cells from MHC-matched or syngeneic donors that have not been primed with antigen. Disease can be prevented by the co-transfer of CD4+ CD45RB/low T cells. These data suggest that mice (and other organisms as well) harbor potentially pathogenic CD4+ T cells, as well as regulatory CD4+ T cells that can prevent IBD. During the previous grant period, we showed that migration of T cells to the intestine and disease pathogenesis require bacterial flora, implying that T cell recognition of bacterial antigens is important for disease in this model. We also showed that expansion of T cells in the host intestine is an antigen driven process, and that predominant T cell clones in the immune deficient host are distributed widely in the body. Here we propose four specific aims to further characterize pathogenic and disease preventing T cells. In the first aim, we will use flow cytometry as well as genetically or immunologically modified recipients to explore where the initial activation of donor T cells occurs following transfer, where the cells undergo replication, and where antigen prevention must occur for disease pathogenesis. In the second aim, we will determine if disease can be induced to antigens that are not of bacterial origin. Cells from TCR transgenic mice will be transferred to immune deficient recipients that have been given antigen in various forms, or which express it as a transgene. In this way, we hope to define the dose and distribution of antigen required for colitis pathogenesis, and what factors in addition to specific antigen may be required. In the third aim, we will explore the role of NK T cells, from both naive and lipid antigen primed mice, in the prevention of disease pathogenesis. In the fourth aim, we will attempt to better define regulatory or disease preventing lymphocyte pathogenesis. In the fourth aim, we will attempt to better define regulatory or disease preventing lymphocyte populations and we will determine if these cells must act by migrating to the intestine. Data from the proposed experiments will add significantly to our knowledge of where pathogenic T cells encounter antigen, where they traffick, what they recognize, and what elements of the immune system, contribute to the prevention of intestinal inflammation. These results should help in the development of new approaches for the prevention of IBD.
Showing the most recent 10 out of 277 publications
