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*
Department of Medicine, Section of Gastroenterology, Veterans Administration Lakeside Medical Research Center and Northwestern University Medical School, Chicago, IL 60611;
Department of Immunology, University of Washington, Seattle, WA 98195; and
Ben May Institute for Cancer Research, Committee on Immunology and the Department of Pathology, University of Chicago, Chicago, IL 60637
To examine the effect of self Ag on activation requirements of
TCR-
ß intestinal intraepithelial lymphocytes (IELs), we utilized
the 2C transgenic (Tg) mouse model specific for a peptide self Ag
presented by class I MHC, H-2Ld. CD8 and
CD4-CD8- IELs from syngeneic
(H-2b, self Ag-) and self Ag-bearing
(H-2b/d, self Ag+) strains were examined for
their ability to respond in vitro to P815 (H-2d) cell lines
expressing the endogenous antigenic peptide, p2Ca. Proliferation,
cytokine production, and CTL activity were elicited in IEL T cells
isolated from self Ag- H-2b mice when
stimulated with P815 cells expressing basal levels of self Ag. These
responses were enhanced following the addition of exogenous p2Ca
peptide and ectopic expression of the costimulatory molecule, B7-1. By
comparison, IEL from self Ag-bearing mice failed to respond to basal
levels of self Ag presented by P815 cells even in the presence of
B7-1-mediated costimulation. However, the addition of increasing
amounts of exogenous p2Ca peptide induced a response from the in vivo
"tolerized" T cells. These results suggest that exposure to self Ag
in vivo increased the threshold of TCR activation of Ag-exposed
self-reactive IELs. The dependence of increased signal 1 to activate
self-reactive IELs suggests a defect in TCR signaling that may maintain
self tolerance in vivo. These data suggest that conditions that
overcome signal 1 IEL defects may initiate autoreactive responses in
the intestine.
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