Intestinal epithelial antigen induces mucosal CD8 T cell tolerance, activation, and inflammatory response.
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 (Fabpl(4x 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-gamma-, 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 Fabpl(4x 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.
Liu
Zhanju
Z
Division of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Lefrançois
Leo
L
D000208:Acute Disease; D000284:Administration, Oral; D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000096:biosynthesis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D004760:Enterocolitis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology; D050556:Fatty Acid-Binding Proteins; D006801:Humans; D007108:Immune Tolerance; D018928:Immunity, Mucosal; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000473:pathology*; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000235:genetics / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008643:Mesentery; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D010581:Peyer's Patches / Q000166:cytology / Q000276:immunology
D001324:Autoantigens; D002352:Carrier Proteins; D018984:Epitopes, T-Lymphocyte; D050556:Fatty Acid-Binding Proteins; D010047:Ovalbumin