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Departments of
*
Pediatrics and
Internal Medicine and
Sealy Center for Molecular Sciences, University of Texas Medical Branch, Galveston, TX 77555
One of several routes of achieving immunologic tolerance is through
functional inactivation of Ag-specific T cells. Oral administration of
Ag can allow survival of the Ag-specific T cells that are functionally
anergic. The aim of this study was to investigate whether functional
inactivation of Ag-specific T cells is directed through an activation
process and to further define the differentiative pathways and
functional characteristics of anergic T cells. Mice were transplanted
with OVA-specific TCR-transgenic T cells and either fed OVA or
immunized s.c. with the OVA peptide 323339 in CFA. OVA-specific T
cells from OVA-fed mice were unresponsive to restimulation in vitro
within 4872 h after treatment. In vivo, however, T cell proliferation
was detected by 5,6-carboxy-succinimidyl-fluoresceine-ester intensity
changes in OVA-specific T cells. The mesenteric lymph nodes (LNs) from
OVA-fed mice more frequently contained OVA-specific dividing cells in
vivo than those in the peripheral LNs, and the reciprocal was observed
following s.c. immunization of the OVA peptide in CFA. The induction of
anergy in OVA-fed mice was accompanied by rapid up-regulation of CD69
and CTLA-4, later down-regulation of CD45RB on OVA-specific T cells,
and a marked decrease in T cell secretion of IL-2, IL-10, and IFN-
after OVA restimulation in vitro. Results from this study indicate that
the inductive phase of oral tolerance is preceded by Ag-specific T cell
activation in vivo, proliferation in the regional draining LNs, and
differentiation into a memory-like state. These results indicate that
Ag-directed differentiation occurs as a part of T cell tolerance
through anergy.
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