Because the development of insulitis and diabetes is predictable inLyp/Lypcongenic BB rats, we have characterized early islet inflammation in these rats to determine the cell subsets involved in the onset of autoimmune insulitis. Pancreas sections from prediabeticLyp/Lyp, Lyp/+ and +/+ rats were analyzed by immunohistochemistry. We found W3/25+ cells in the exo-and endocrine tissue from all three genotypes, but intraislet insulitis was never found inLyp/+ or +/+ rats. The onset of massive, intraislet B- and T-cell infiltration inLyp/Lyprats was preceded byRelB+ cells in and around the islets, followed by ED1+ monocytes/macrophages.RelB+ cells were more frequent in the parafollicular cortex of pancreatic lymph nodes fromLyp/Lypthan fromLyp/+ and +/+ rats. In theLyp/Lypthymus, we found significantly increased expression of IL-12p40 messenger RNA (mRNA;p< 0.001), located in theRelB-protein-rich corticomedullary junction. The NF-&kgr;B/RelB complex specifically transactivates genes involved in antigen presentation in dendritic cells.RelB+ cells in the islets may therefore mark the onset of autoimmune insulitis and antigen-specific activation of autoreactive T cells in the lymph nodes of diabetes proneLyp/LypBB rats. In the thymus,RelB+ cells may support theLyp-dependent development of self-reactive thymocytes by activation of cytokine expression.