Journal of Leukocyte Biology
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1103534

Received for publication November 4, 2003.

Accepted for publication November 11, 2003.

Article

Effects of cholera toxin on innate and adaptive immunity and its application as an immunomodulatory agent

Ed C. Lavelle @, Andrew Jarnicki , Edel McNeela , Michelle E. Armstrong , Sarah C. Higgins , Olive Leavy , and Kingston H. G. Mills

Immune Regulation Research Group, Department of Biochemistry, Trinity College, Dublin, Ireland

@ To whom correspondence should be addressed. E-mail: lavellee{at}tcd.ie.


  Abstract

Cholera toxin (CT) is a potent vaccine adjuvant when administered via parenteral, mucosal, or transcutaneous routes. It also inhibits innate inflammatory responses induced by pathogen-derived molecules, such as lipopolysaccharide (LPS). We demonstrated previously that CT promotes the induction of regulatory type 1 T cells (Tr1) as well as T helper type 2 cells (Th2). T cells from mice immunized with antigen in the presence of CT produced high levels of interleukin (IL)-10 and IL-5 and low levels of IL-4 and interferon-{gamma} (IFN-{gamma}). Here, we demonstrate that immunization with antigen in the presence of CT induced a population of antigen-specific CD4+ T cells that produced IL-10 in the absence of IL-4, in addition to cells that coexpressed IL-4 and IL-10 or produced IL-4 only. CT-generated Tr1 cells inhibited antigen-specific proliferation as well as IFN-{gamma} production by Th1 cells, and this suppression was cell contact-independent. It is interesting that coincubation with Th1 cells significantly enhanced IL-10 production by the Tr1 cells. As IL-10 can promote the differentiation of Tr1 cells, we investigated cytokine production by dendritic cells (DC) following exposure to CT. Previous data showed that CT can modulate the expression of costimulatory molecules and inhibit the production of chemokines and cytokines, including IL-12 and tumor necrosis factor {alpha} and enhance IL-10 production. Here, we show that CT synergizes with LPS to induce IL-6 and IL-1{beta} in addition to IL-10 production by immature DC. Therefore, CT may promote the induction of Th2 and Tr1 cells in part via selective modulation of DC cytokine production and costimulatory molecule expression.

Key Words: regulatory T cell • dendritic cell • innate immunity • vaccination • tolerance/suppression/anergy • Th1/Th2 cell




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