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Departments of
*
Oral Biology and
Microbiology, Immunobiology Vaccine Center, University of Alabama Medical Center, Birmingham, AL 35294;
Department of Clinical Bio-regulatory Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan; and
§
Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
CD40 ligand (CD40L) gene-disrupted (CD40L-/-) mice
were employed to examine the role of costimulatory signals via
CD40L-CD40 interactions in mucosally induced tolerance.
CD40L-/- and control (CD40L+/+) mice of the
same C57BL/6 x 129/J background were immunized orally with 25 mg
of OVA before systemic challenge with OVA in CFA. While
CD40L+/+ mice showed reductions in Ag-specific T cell
responses including delayed-type hypersensitivity (DTH) and
proliferative responses, CD40L-/- mice underwent normal T
cell responses. Further, cytokine analysis of splenic CD4+
T cells showed that both Th1-type (e.g., IFN-
and IL-2) and Th2-type
(e.g., IL-4, IL-5, IL-6, and IL-10) responses were maintained in
CD40L-/- mice orally immunized with OVA, whereas these
cytokine responses in CD40L+/+ mice were significantly
reduced. In addition, splenic CD4+ T cells from
CD40L-/- mice orally immunized with OVA provided B cell
help in Ag-specific Ab-forming cells when the cells were cultured with
naive B cells in the presence of Ag and CD40L-transfected cell lines.
In contrast, an identical culture condition containing splenic
CD4+ T cells from orally tolerized CD40L+/+
mice did not exhibit helper activity. Taken together, these findings
indicate that CD40L and CD40 interactions are essential for the
induction of systemic T cell unresponsiveness to orally administered
Ag.
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