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Blood, 1 May 2006, Vol. 107, No. 9, pp. 3632-3638.
Prepublished online as a Blood First Edition Paper on January 5, 2006; DOI 10.1182/blood-2005-11-4497.
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Submitted November 14, 2005
Accepted December 20, 2005
Vasoactive intestinal peptide generates human tolerogenic dendritic cells that induce CD4 and CD8 regulatory T cells
Elena Gonzalez-Rey, Alejo Chorny, Amelia Fernandez-Martin, Doina Ganea, and Mario Delgado*
Institute of Parasitology and Biomedicine, CSIC, Granada, Spain
Dept. of Biological Sciences, Rutgers University, Newark, NJ, USA
* Corresponding author; email: mdelgado{at}ipb.csic.es.
Induction of antigen-specific tolerance is critical for autoimmunity prevention and immune tolerance maintenance. In addition to their classical role as sentinels of the immune response, dendritic cells (DCs) play important roles in maintaining peripheral tolerance through the induction/activation of regulatory T cells (Tr). The possibility to generate tolerogenic DCs opens new therapeutic perspectives in autoimmune/inflammatory diseases. The characterization of endogenous factors that contribute to the development of tolerogenic DCs is highly relevant. We here report that the immunosuppressive neuropeptide, vasoactive intestinal peptide (VIP), induces the generation of human tolerogenic DCs with the capacity to generate CD4 and CD8 Tr from their respective naive subsets. The presence of VIP during the early stages of DC differentiation from blood monocytes generates a population of IL-10-producing DCs unable to fully mature following inflammatory stimuli. CD4 Tr generated with VIP-differentiated DCs resemble the previously described Tr1 in terms of phenotype and cytokine profile. CD8 Tr generated with tolerogenic VIP-DCs have increased numbers of IL-10-producing CD8+CD28-CTLA4+ T cells. Both CD4 and CD8 Tr suppress primarily antigen-specific Th1-mediated responses. Therefore, the possibility to generate/expand ex vivo tolerogenic DCVIP opens new therapeutic perspectives for the treatment of autoimmune diseases and allogeneic transplantation in humans.
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