The intestinal epithelium functions to absorb nutrients and to protect the organism against microbes. To prevent autoimmune attack on this vital tissue, T cell tolerance to intestinal self-antigens must be established. Central tolerance mechanisms involve medullary thymic epithelial cells (mTECs), which use endogenously expressed peripheral-tissue antigens (PTAs) to delete self-reactive thymocytes. The prevailing model for the induction of peripheral tolerance involves cross-presentation of tissue antigens by quiescent dendritic cells. Here we show that lymph node stromal cells present endogenously expressed PTAs to T cells. Moreover, antigen presentation by lymph node stroma is sufficient to induce primary activation and subsequent tolerance among CD8(+) T cells. Thus, lymph node stromal cells are functionally akin to mTECs and provide a direct strategy for purging the peripheral repertoire of self-reactive T cells.

The autoimmune cascade that culminates in diabetes initiates within pancreatic lymph nodes (PLNs). Here, we show that developmentally controlled lymphogenesis establishes a preferential trafficking route from the gut to the PLN, where T cells can be activated by antigens drained from the peritoneum and the gastrointestinal tract. Furthermore, intestinal stress modifies the presentation of pancreatic self-antigens in PLNs. The convergence of endocrine and intestinal contents within PLNs has significant implications for type 1 diabetes and may help to explain the link between autoimmune pathogenesis and environmental provocation.autoimmunity ͉ diabetes ͉ peritoneal lymphatics ͉ enteropathy T ype 1 diabetes (T1D) is an autoimmune disorder characterized by destruction of the insulin-producing ␤ cells of the endocrine pancreas. The first stage of disease, known as insulitis, entails leukocyte invasion of the pancreatic islets; the second stage, overt diabetes, is marked by massive death of islet ␤ cells and the subsequent loss of glucose homeostasis (1). The immune assault on ␤ cells that preludes diabetes is orchestrated by T cells. Naïve, ␤ cell-reactive T cells initially encounter their cognate antigen in pancreatic lymph nodes (PLNs) (2). Islet antigens are shuttled to these nodes by CD11b ϩ dendritic cells and subsequently presented to T lymphocytes (3). Thus, PLNs are key to diabetes pathogenesis (4, 5), the location where tolerance to pancreatic self-antigens is first broken.Environmental factors impinge on an individual's genetic susceptibility to type 1 diabetes (6). Alimentary agents such as enteroviruses (e.g., coxsackie virus) and dietary antigens (e.g., gluten) are associated with T1D (7-13), and there is a frequent association between T1D and celiac disease (14). However, the precise mechanisms by which these factors might influence the autoimmune response to pancreatic ␤ cells remain elusive. The common entry route of such environmental components certainly raises the question of how the gastrointestinal tract relates to the pancreatic axis. Materials and MethodsMice. All mice were bred and maintained under barrier conditions in the Joslin Diabetes Center animal facility in accordance with National Institutes of Health guidelines. BDC2.5͞NOD, OT-I͞Rag-1 0 , and OT-II TCR transgenic (tg) mice are described in refs. 15-17. NOD, NOD͞SCID, and B6.H2 g7/g7 mice were bred at the Joslin Diabetes Center animal facility, and B6 mice were obtained from The Jackson Laboratory.Antigens. Mice were injected i.p., intragastrically, or i.v. with chicken ovalbumin (OVA) (Sigma), BSA (Sigma), or saline (as controls), and OVA-coated beads, OVA-loaded apoptotic cells, or purified pancreatic islets. Soluble OVA was adsorbed onto 0.5-m polystyrene microparticles (beads) (Polysciences) according to the manufacturer's protocol. Purified pancreatic islets were purified from 4-to 6-week-old NOD mice at the Islet Core of the Juvenile Diabetes Research Foundation Center at Harvard Medical School and were resuspended in PBS for in...