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J. Exp. Med.,
Volume 189, Number 3, February 1, 1999 541-552
1 and 2 Chain Expression
By
From the * Immune Cell Interaction Unit, Mucosal Immunity Section, and the Cholera toxin (CT) is a potent mucosal vaccine adjuvant, which has been shown to induce T
helper cell type 2 (Th2) responses in systemic and mucosal tissues. We report that CT inhibits
the production of interleukin (IL)-12, a major Th2 counterregulatory cytokine. IL-12 p70 production by stimulated human monocytes was inhibited by CT in a dose-dependent manner.
This suppression occurred at the level of gene transcription, was maximal at low concentrations of CT, and was dependent on the A subunit of the toxin, since purified CT B subunit had
minimal effect. CT also inhibited the production of IL-12 p70 by monocyte-derived dendritic
cells, as well as the production of tumor necrosis factor Clinical Immunology
Section, Laboratory for Clinical Investigation, National Institutes of Allergy and Infectious Disease,
National Institutes of Health, Bethesda, Maryland 20892
, but not IL-10, IL-6, or transforming
growth factor (TGF)-
1, by stimulated monocytes. The effects of CT were not due to autocrine production of IL-10, TGF-1, or prostaglandin E2. CT inhibited the production of IFN-
by anti-CD3-stimulated human peripheral blood mononuclear cell, due in part to suppression
of IL-12 production, but also to the inhibition of expression of the 1 and 2 chains of the IL-12 receptor on T cells. In vivo, mice given CT before systemic challenge with lipopolysaccharide
had markedly reduced serum levels of IL-12 p40 and interferon . These data demonstrate two
novel mechanisms by which CT can inhibit Th1 immune responses, and help explain the ability of mucosally administered CT to enhance Th2-dependent immune responses.
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