Generating tolerogenic dendritic cells with neuropeptides Mario Delgado* Instituto de Parasitologia y Biomedicina, Consejo Superior de Investigaciones Cientificas, Granada 18100, Spain ARTICLE INFO Article history: Received 23 December 2008 Accepted 29 January 2009 Available online 4 February 2009 Keywords: Tolerance Dendritic cell Autoimmunity Regulatory T cells Neuropeptide ABSTRACT Induction of antigen-specific tolerance is critical to prevent autoimmunity, to maintain immune homeostasis, and to achieve transplant tolerance. In addition to their classic role as sentinels of the immune response, dendritic cells (DCs) play important roles in maintaining peripheral tolerance through the induction/activation of regula- tory T (Treg) cells. The possibility of generating tolerogenic DCs opens new therapeutic perspectives in autoimmune and inflammatory diseases. Characterizing endogenous factors that contribute to the develop- ment of tolerogenic DCs is highly relevant. Some neuropeptides that are produced during the ongoing inflammatory response have emerged as endogenous anti-inflammatory agents that participate in the regulation of the processes that ensure self-tolerance. Here, we examine the latest research findings indicat- ing that the role of these neuropeptides in immune tolerance is partially mediated through differential effects on DC functions, which depend on the differentiation and activation states. Importantly, neuropeptides such as vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, and melanocyte- stimulating hormone have demonstrated an ability to induce tolerogenic DCs with the capacity to generate CD4 and CD8 Treg cells. The possibility of generating or expanding ex vivo tolerogenic DCs with neuropeptides indicates the therapeutic potential for autoimmune diseases and graft-versus-host disease after allogeneic transplantation in humans.  2009 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. 1. Dendritic cells at the crossroads between immune defense and immune tolerance The immune system responds to pathogen invasion with two temporarily separate but physically linked responses, mediated by different types of cells. The innate immune response is initiated rap- idly based on the recognition of conserved pathogen-associated mo- lecular patterns and involves neutrophils, monocytes/macrophages, and dendritic cells (DCs) in the periphery and microglia in the central nervous system (CNS). The second response, termed adap- tive immunity, occurs later, generates memory for a specific anti- gen, and depends on the activation of T and B lymphocytes through specific receptors. DCs are a heterogeneous population of professional antigen- presenting cells that play a critical role in the cross-talk between the innate and adaptive arms of the immune system [1]. DCs par- ticipate in the first line of defense against environmental pathogens in nonlymphoid organs, such as the skin, gastrointestinal tract, and airways. DCs act as innate immune cells capable of phagocytosis and release of proinflammatory agents and initiate the adaptive immune response by activating antigen-specific naive T cells. Fol- lowing pathogen recognition, DCs mature, acquiring the capacity to migrate to secondary lymphoid organs, where they activate naive T cells by providing both stimulatory and costimulatory signals [1]. Obviously, the regulation of their maturation, migration, and expres- sion of stimulatory and costimulatory molecules has major conse- quences on the immune response, and some forms of immunointer- vention to treat immune disorders have tried to target DCs [2]. In addition to their classic role as sentinels of the immune response, recent evidence indicates that various populations of DCs are central to orchestration of the control of immune tolerance [3]. Safe induction of antigen-specific long-term tolerance is critical to maintain immune homeostasis, prevent unnecessary immune re- sponses, and control self-reactive T cells on autoimmune diseases. Intrinsic control of lymphocytes is exerted, for example, by central clonal deletion of self-reactive T cells in the thymus via apoptosis of immature self-reactive lymphocytes upon exposure to self-antigen or activation-induced cell death of mature effector cells. However, although essential, central tolerance is not sufficient and additional mechanisms exist in the periphery to suppress self-reactive lym- phocytes that escape to negative selection in the thymus. Among them, the generation of antigen-specific regulatory T cells (Treg) with suppressive activity seems to play a critical role in the induc- tion of peripheral tolerance [4–6]. Two major types of Treg cells have been characterized in the CD4 + population on the basis of their origin, generation, and mechanism of action (i.e., the naturally occurring, thymus-generated forkhead box P3 (FoxP3)-expressing CD25 + Treg cells and the peripherally induced Treg cells, which are composed of interleukin (IL)-10-secreting Tr1 cells, transforming growth factor- (TGF-)-secreting Treg cells, and inducible FoxP3 + * Corresponding author. E-mail address: mdelgado@ipb.csic.es (M. Delgado). Human Immunology 70 (2009) 300-307 Contents lists available at ScienceDirect 0198-8859/09/$32.00 - see front matter  2009 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.humimm.2009.01.020