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The Journal of Immunology, 1999, 162: 1904-1909.
Copyright © 1999 by The American Association of Immunologists

Mucosally Induced Systemic T Cell Unresponsiveness to Ovalbumin Requires CD40 Ligand-CD40 Interactions1

Mi-Na Kweon*, Kohtaro Fujihashi2,*, Yoshio Wakatsuki{ddagger}, Toshiya Koga*, Masafumi Yamamoto§, Jerry R. McGhee{dagger} and Hiroshi Kiyono*

Departments of * Oral Biology and {dagger} Microbiology, Immunobiology Vaccine Center, University of Alabama Medical Center, Birmingham, AL 35294; {ddagger} 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-{gamma} 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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