Pathogenesis and Prevention of Type I Diabetes in the Nod Mouse and Man

Davis, Mark

Abstract

One of the most puzzling aspects of any spontaneous auto-immune disease is how it is initiated. In order to address this issue in the non-obese diabetic (NOD) mouse model, we have isolated CD4+ T cells from the earliest cell infiltrates (day 14-18) and analyzed alpha beta TCR usage from single cells. We find at least three distinct sequence motifs that are enriched in these T cells compared with lymph nodes and have ben re- constructing these specificities in indicator T cells. We intend to determine the specificities of these TCR heterodimers and others that may emerge. The target antigens for these cells may hold important clues as to the origins of autoimmunity in these mice and perhaps be relevant to human type I diabetes as well. We will also follow these TCR types through different time points for clues as to how the T cell repertoire may be changes as insulitis progresses into disease. We will compare these data with those for NOR mice which can only get insulitis. If we identify novel antigenic targets of these cells we will collaborate with the Chien lab to make peptide/IA tetramers to follow their time course and phenotype. As there is abundant evidence that CD8+ T cells play a role in disease progression we will also survey CD8+ Tcr useage at various time points as well. If we find evidence of restricted useage, as we have for CD4+ T cells, we will also try to identify the antigen/restriction element involved. Finally, through a collaboration with the Goodnow lab, we will make TCR transgenics using these dominant motif alpha beta pairs in order to determine whether have large numbers of these particular T cells will accelerate, decelerate or have no effects on the progression to disease in vivo.