How tolerogenic dendritic cells induce regulatory T cells

Abstract

Since their discovery by Steinman and Cohn in 1973, dendritic cells (DCs) have become increasingly recognized for their crucial role as regulators of innate and adaptive immunity. DCs are exquisitely adept at acquiring, processing, and presenting antigens to T cells. They also adjust the context (and hence the outcome) of antigen presentation in response to a plethora of environmental inputs that signal the occurrence of pathogens or tissue damage. Such signals generally boost DC maturation, which promotes their migration from peripheral tissues into and within secondary lymphoid organs and their capacity to induce and regulate effector T cell responses. Conversely, more recent observations indicate that DCs are also crucial to ensure immunological peace. Indeed, DCs constantly present innocuous self- and nonself-antigens in a fashion that promotes tolerance, at least in part, through the control of regulatory T cells (Tregs). Tregs are specialized T cells that exert their immunosuppressive function through a variety of mechanisms affecting both DCs and effector cells. Here, we review recent advances in our understanding of the relationship between tolerogenic DCs and Tregs.

Figure 1. Types of tolerogenic DCs and their mechanisms of action

Tolerogenic DCs (tDCs) participate to the establishment of T cell tolerance by a variety of mechanisms, including the induction of anergy, deletion of antigen-reactive T cells, stimulation of suppressive regulatory T cells (Tregs) either by activation of existing Tregs or de novo differentiation of Tregs from Tns and production of anti-inflammatory cytokines and other factors. Depending on the differentiation state of the DC and the site of tolerogenic instruction, tDCs can be separated in natural tolerogenic DCs (ntDCs) and induced tolerogenic DCs (itDCs). The steady state environment instructs ntDCs (and includes iDCs) while itDCs arise during pathologies or after manipulation.

Figure 2. Relationship of maturation status, tolerogenicity and immunogenicity among DC subsets

Immature DCs (iDCs) receive activation signals from microbial byproducts or tissue distress to acquire a mature phenotype, including the ability to migrate to lymph nodes and enhanced antigen presentation and costimulatory capacities. These mature DCs are highly stimulatory (sDC) and induce effector responses. Tolerogenic DCs (tDCs) include most iDCs but also comprise some cells with advanced maturation status. Only iDCs can give rise to mDCs. mDCs may loose their immunostimulatory capacity to become exhausted (exDC), however, their role in the induction of Tregs remains uncertain.

Figure 3. Education of immunogenic or tolerogenic DCs by environmental signals

Immature DCs (iDCs) perceive a myriad of inputs leading to their differentiation into sDCs or tDCs. Upon engagement of danger signal receptors by microbes or cellular distress, the presence of activating cytokines or changes in the abundance of certain metabolites, these cells mature and become sDCs that migrate to the draining secondary lymphoid organs (SLOs) using CCR7. Through presentation of cognate antigen and costimulatory surface receptors as well as production of cytokines and the regulation of metabolites, sDCs coerce naïve T cells (Tns) to become effector cells (Teffs). On the other hand, at steady state, commensals and structural cells produce anti-inflammatory cytokines that in combination with regular levels of metabolites and minute quantities of danger signals imprint tDCs to migrate to SLOs using CCR7. Upon contact with antigen specific cells, tDCs induce the differentiation of regulatory T cells (Tregs) through a variety of mechanisms. Toll-like receptors (TLR), Nod-like receptors (NLR), RigI-like receptors (RLR), mammalian target of rapamycin (mTOR), 1,25-dihydroxyvitamin D3 (1,25D3), thymic stromal lymphoietin (TSLP), hepatocyte growth factor (HGF), vasoactive intestinal peptide (VIP), Glucocorticoid (GC), all-trans retinoic acid (RA), prostaglandin E2 (PGE2), vascular endothelial growth factor (VEGF), programmed death-1 ligand (PDL), carbon monoxide (CO), Commensal (Comm).

Figure 4. Induced-tolerogenic DCs

DCs progenitors (preDCs) and immature DCs (iDCs) from multiple sources are susceptible to tolerogenic instruction by multiple strategies. These cells can be used as therapeutic tools for the induction of antigen specific tolerance.