Journal of Leukocyte Biology
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Published online before print June 18, 2008
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1207850

Received for publication December 21, 2007.
Revised April 14, 2008.
Accepted for publication May 23, 2008.

Article

Cholera toxin B subunit promotes the induction of regulatory T cells by preventing human dendritic cell maturation

Antonella D'Ambrosio , Manuela Colucci , Orsola Pugliese , Francesca Quintieri , and Monica Boirivant @

Immune-Mediated Section, Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanita, Rome, Italy

@ To whom correspondence should be addressed. E-mail: monica.boirivant{at}iss.it.


  Abstract

Cholera toxin B subunit (CTB) is an efficient mucosal carrier molecule for the generation of immune responses to linked antigens. There is also good evidence that CTB acts as an immunosuppressant, as it is able to down-modulate human monocyte/macrophage cell line activation and to suppress Th1-type responses. In the present study, we examined the possibility that recombinant CTB (rCTB) may affect human dendritic cell (DC) functions in response to LPS stimulation and may induce the generation of DC with the capacity to generate CD4+ regulatory T cells (Tregs). Our findings show that rCTB partially prevents the LPS-induced maturation process of monocyte-derived DC (MDDC) and decreases their IL-12 production with no relevant effect on IL-10 production. LPS-stimulated MDDC pretreated with rCTB are able to promote the induction of low, proliferating T cells, which show an enhanced IL-10 production associated with a reduced IFN-{gamma} production and the same high levels of TGF-{beta} as the control. These T cells suppress proliferation of activated autologous T cells. Transwell experiments and blockade of IL-10R and TGF-{beta} showed that the immunomodulatory effect is mediated by soluble factors. Thus, T cells induced by rCTB-conditioned MDDC acquire a regulatory phenotype and activity similar to those described for type 1 Tregs.

Key Words: antigen-presenting cells • cytokines • tolerance






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