Transfer of CD4+ CD45RB high T cells into immunodeficient mice results in both the expansion of the transferred T cells and colitis. Here we show that colitis pathogenesis requires expression of MHC class II molecules by the immune-deficient host. Analysis of the TCRβ repertoire of the cells found in the large intestine of diseased mice revealed a population with restricted TCR diversity. Furthermore, nucleotide sequence analysis demonstrated the selection for particular CDR3β amino acid sequence motifs. Collectively, these data indicate that the expansion of T cells in the intestine and colitis pathogenesis are likely to require the activation of Ag-specific T cells, as opposed to nonspecific or superantigen-mediated events. There is relatively little overlap, however, when the TCR repertoires of different individuals are compared, suggesting that a number of Ags can contribute to T cell expansion and the generation of a T cell population in the intestine. Surprisingly, many of the expanded clones found in the large intestine also were found in the spleen and elsewhere, although inflammation is localized to the colon. Additionally, donor-derived T cells appear to be activated in both the intestine and the spleen at early time points after cell transfer. Together, these results strongly suggest that disease induction in this model involves either the early and systemic activation of antigen-specific T cells or the rapid dispersal of T cells activated at a particular site.