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Division of Immunology, University of Connecticut Health Center, Farmington, CT 06030
Intestinal autoimmune diseases are thought to be associated with a breakdown in tolerance, leading to mucosal lymphocyte activation perhaps as a result of encounter with bacterium-derived Ag. To study mucosal CD8+ T cell activation, tolerance, and polarization of autoimmune reactivity to self-Ag, we developed a novel (Fabpl4x at –132-OVA) transgenic mouse model expressing a truncated form of OVA in intestinal epithelia of the terminal ileum and colon. We found that OVA-specific CD8+ T cells were partially tolerant to intestinal epithelium-derived OVA, because oral infection with Listeria monocytogenes-encoding OVA did not elicit an endogenous OVA-specific MHC class I tetramer+CD8+ T cell response and IFN-
-, IL-4-, and IL-5-secreting T cells were decreased in the Peyer’s patches, mesenteric lymph nodes, and intestinal mucosa of transgenic mice. Adoptive transfer of OVA-specific CD8+ (OT-I) T cells resulted in their preferential expansion in the Peyer’s patches and mesenteric lymph nodes and subsequently in the epithelia and lamina propria but failed to cause mucosal inflammation. Thus, CFSE-labeled OT-I cells greatly proliferated in these tissues by 5 days posttransfer. Strikingly, OT-I cell-transferred Fabpl4x at –132-OVA transgenic mice underwent a transient weight loss and developed a CD8+ T cell-mediated acute enterocolitis 5 days after oral L. monocytogenes-encoding OVA infection. These findings indicate that intestinal epithelium-derived "self-Ag" gains access to the mucosal immune system, leading to Ag-specific T cell activation and clonal deletion. However, when Ag is presented in the context of bacterial infection, the associated inflammatory signals drive Ag-specific CD8+ T cells to mediate intestinal immunopathology.
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