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

Immunoglobulin-like transcript 3: A crucial regulator of dendritic cell function

Dendritic cells (DC) are key components of the immune system, which actively participate in innate and adaptive immune responses. They are traditionally viewed as the immunologic centerpiece that is able to prime CD4 helper and CD8 cytotoxic T-cell effector populations. However, accumulated evidence highlights the functional plasticity of DC, which are shown to also be able to display a tolerogenic function eliciting the differentiation of T suppressor (Ts) and regulatory (Treg) cells. This tolerogenic state of DC is characterized by low costimulatory potential and high expression of inhibitory receptors. Conspicuously among the latter is the immunoglobulin-like transcript 3 (ILT3), which independently prevents the activation of both DC and T cells. DC overexpressing ILT3 display lower phosphorylation levels of NF-B and fail to stimulate the full program of Th proliferation and maturation eliciting instead the differentiation of CD8 TS and CD4 Treg. In contrast, ILT3-knockdown DC have robust cytokine and chemokine production, and are able to trigger stronger T-cell responses to viral antigens or alloantigens. Understanding and manipulating the functional immunogenic/tolerogenic dichotomy of DC has important clinical applications for achieving tolerance in organ transplantation, stemming autoimmune diseases or, conversely, generating efficient immunogenic vaccines for immunotherapy in cancer and chronic viral diseases