Tolerogenic dendritic cells in cancer, transplantation, and autoimmune diseases

Over the last decade the notion has prevailed that immature, quiescent dendritic cells (DC) induce tolerance, whereas activated mature DC induce immunity. Mature DC were long known to be essential in the “instruction” of effector CD4 and CD8 T cells. Upon T cell receptor (TCR) triggering by major histocompatibility complex (MHC) peptide complexes on the surface of antigen-presenting cells (APC), T cells become activated, and via interaction with costimulatory molecules expressed by APC and exposure to environmental cytokines, they acquire immune functions. The absence of cell surface markers characteristic for a tolerogenic phenotype in rodents has significantly limited research in the field of tolerogenic DC. Progress has been further hampered by the finding that naturally occurring CD4CD25 FOXP3 regulatory T cells are the principal mediators of tolerance to self and allogeneic tissues in rodents, and that they act directly on antigen-stimulated T cells, inhibiting their functional maturation in a DC-independent manner. The picture that emerged was that CD4 helper and CD8 cytotoxic T cells are antigen specific, whereas CD4CD25regulatory T cells are not antigen specific, displaying their silencing, inhibitory functions through direct T–T cell interactions. A peace-keeping force without a specific task was thus assumed to pacify the immunologic world for better (in autoimmunity) or for worse (in infection). Evidence that CD8 T suppressor cells act in an antigenspecific, MHC class I–restricted manner, inhibiting the capacity of APCto upregulate costimulatory molecules, yet enhancing the expression of the DC-specific inhibitory receptors ILT3 and ILT4 came from in vitro studies on human APC. Thus, it became apparent that similar to CD4andCD8immuneeffector cells,CD4andCD8regulatory/suppressor T cells act also in an antigen-specific manner, aswouldbe expected for any component of the adaptive immune response. It is now widely accepted that the immune response can be inhibited by various CD4 and CD8 regulatory (Treg) and suppressor (Ts) cells that participate in innate and adaptive immunity [1–7]. Natural Treg develop in the thymus and inhibit immune responses in an Ag-nonspecific, MHC-nonrestricted manner, via an APC-independent process [1–3,8], whereas adaptive Treg are Ag induced, develop in the periphery, and exert their function either by secreting inhibitory cytokines (interleukin [IL]–10 and transforming growth factor [TGF]–) or by tolerizing APC directly by cell-to-cell interaction [9–14]. We shall first review some well established notions pertaining to the functional maturation of different DC subsets, and we shall then summarize the important conclusions reached by contributors to this special issue.