Immunology and Cell Biology (2002) 80, 477–483 Special Feature Immature, but not inactive: the tolerogenic function of immature dendritic cells KARSTEN MAHNKE, 1 EDGAR SCHMITT, 2 LAURA BONIFAZ, 3 ALEXANDER H ENK 1 and HELMUT JONULEIT 1 1 Department of Dermatology and 2 Institute of Immunology, University of Mainz, Mainz, Germany and the 3 Laboratory of Cellular Immunology and Physiology, The Rockefeller University, New York, USA Summary The induction of antigen-specific T cell tolerance and its maintenance in the periphery is critical for the prevention of autoimmunity. Recent evidence shows that dendritic cells (DC) not only initiate T cell responses, but are also involved in silencing of T cell immune responses. The functional activities of DC are mainly dependent on their state of activation and differentiation, that is, terminally differentiated mature DC can efficiently induce the development of T effector cells, whereas immature DC are involved in maintenance of peripheral tolerance. The means by which immature DC maintain peripheral tolerance are not entirely clear, however, their functions include the induction of anergic T cells, T cells with regulatory properties as well as the generation of T cells that secrete immunomodulatory cytokines. This review summarizes the current knowledge about the immunoregulatory role of immature DC that might act as guardians for the induction and maintenance of T cell tolerance in the periphery. Key words: autoimmunity, dendritic cells, peripheral tolerance, regulatory T cells. Introduction The adaptive immune system represents a highly effective and dynamic system that protects a host from pathogens. The process of T cell receptor generation is based on random rearrangements and the promiscuity of the resulting receptors bears a high risk for the development of autoreactive T cells. These autoreactive T cells have the ability to respond to autoantigens expressed by different tissues and hence produce an immune reaction against ‘self ’. Therefore, mechanisms of antigen-specific tolerance induction in the periphery of the body are critical for the prevention of autoimmunity and maintenance of immune homeostasis. Central tolerance has been classically ascribed to clonal deletion of self-reactive T cells in the thymus upon interaction with dendritic cells (DC) that display self-antigens. 1,2 How- ever, central tolerance is incomplete, since not all self- antigens gain access to the thymus 3,4 and several self-reactive lymphocytes escape central deletion. Furthermore, the expo- sure of the body to harmless foreign proteins present in the lumen of the airways and intestine do not usually initiate inflammation, instead they will be ‘tolerated’ by the T cells. Therefore, additional mechanisms ensuring tolerance in the periphery must be present. Among them, active silencing or killing of post thymic T cells represent one means by which T cell activation is curbed, another means is the induction of CD4 + CD25 + T regulatory (Treg) cells. This distinct subset of T cells plays a central role for the maintenance of peripheral tolerance by active suppression of effector T cell populations. Regardless of the mechanisms employed for maintenance of peripheral T cell tolerance, a checkpoint is required in decid- ing whether or not potentially self-reactive T cells are to be deleted. Although DC function is traditionally associated with the induction of primary T cell responses, there is increasing evidence that DC perform also a critical role in the induction and maintenance of peripheral tolerance and this review summarizes the current knowledge about the functions of these ‘regulatory’ DC. Dendritic cells as sentinels for the immune system To maintain tolerance as well as immunity, ‘sentinels’ in the periphery of the body are essential. Among leukocytes, DC are perfectly equipped for immune surveillance, since they are located in skin, 5 airways 6,7 as well as in the interstitial spaces of many organs, 8 lymphoid tissues 9,10 and blood. 11,12 The expression of many different adhesion molecules enables these cells to virtually migrate into every tissue of the body and to insert themselves into epithelia 6,13 without breaking the epithelial barrier; possibly after the interaction of CCR6 receptors on DC. 14 Due to this unique distribution of DC throughout all peripheral tissues, DC are perfectly positioned to capture ‘self ’ and environmental antigens and to access the corresponding specific T cells. Two main functional features render DC capable to deter- mine the outcome of a T cell-mediated immune response: 1. Their ability to take up and transport self and non-self anti- gens from peripheral tissues to secondary lymphoid organs. 2. Their ability to establish intense contact with lymph node T cells (mediated by a variety of different adhesion mole- cules as well as T cell costimulatory molecules), resulting in activation or silencing of respective T cells. Correspondence: Dr Karsten Mahnke, Department of Dermatol- ogy, Langenbeckstr. 1, 55101 Mainz, Germany. Email: mahnke@hautklinik.klinik.uni-mainz.de Received 18 June 2002; accepted 18 June 2002.