title: Mucosally induced systemic T cell unresponsiveness to ovalbumin requires CD40 ligand-CD40 interactions.
abstract: 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.
authors.affiliation: Department of Oral Biology, Immunobiology Vaccine Center, University of Alabama Medical Center, Birmingham 35294, USA.
authors.forename: M N
authors.initials: MN
authors.lastname: Kweon
authors.forename: K
authors.initials: K
authors.lastname: Fujihashi
authors.forename: Y
authors.initials: Y
authors.lastname: Wakatsuki
authors.forename: T
authors.initials: T
authors.lastname: Koga
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
authors.forename: J R
authors.initials: JR
authors.lastname: McGhee
authors.forename: H
authors.initials: H
authors.lastname: Kiyono
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics / Q000502:physiology*; D023201:CD40 Ligand; D016207:Cytokines / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D008024:Ligands; D008211:Lymphocyte Cooperation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009061:Mouth Mucosa / Q000276:immunology*; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D014162:Transfection / Q000276:immunology