Dendritic Cells As Inducers of Peripheral Tolerance

Abstract

Mechanisms of tolerance initiated in the thymus are indispensable for establishing immune homeostasis, but they may not be sufficient to prevent tissue-specific autoimmune diseases. In the periphery, dendritic cells (DCs) play a crucial tolerogenic role, extending the maintenance of immune homeostasis and blocking autoimmune responses. We review here these essential roles of DCs in orchestrating mechanisms of peripheral T cell tolerance as determined by targeted delivery of defined antigens to DCs in vivo in combination with various genetic modifications of DCs. Further, we discuss how DC functions empowered by specific delivery of T cell antigens could be harnessed for tolerance induction in clinical settings.

Figure I. Delivery of defined antigens to DCs in vivo using recombinant chimeric antibodies

T cell antigens are included as fusion proteins added to the carboxy termini of the heavy chains of a recombinant chimeric antibody. The murine IgG1 constant regions were additionally engineered to minimize their non-specific binding to Fc receptors and were then combined with the variable regions specific for surface endocytic receptor DEC205 expressed on murine DCs as described in [30].

Figure 1. Experimental identification of tolerogenic functions of various DCs using methods of antigen delivery and genetic mouse models lacking specific types of DCs

(A) Targeting of antigens to DC1 through either DEC205, DNGR-1/CLEC9A or Langerin results in induction of pTreg cells [52, 56, 68]. (B) Targeting of antigens to all cDCs through CD11c results in inefficient induction of pTreg cells because a majority of such DCs are DC2 and lack an ability to efficiently promote a conversion of pTreg cells [55]. (C) BATF3-dependent DC1 are required for pTreg cell induction and in Batf3^−/− mice characterized by a decreased DC1:DC2 ratio, pTreg cells are converted inefficiently despite antigen targeting through DEC205 [55]. (D) Conversion of pTreg cells depends on the DC1:DC2 ratio. The induction of pTreg cells following an antigen targeting through CD11c to all cDCs is restored in Irf4^−/− mice characterized by the increased proportion of DC1 [55]. (E) The Langerin⁺ migratory DCs within DC1 promote pTreg cell induction, and following an ablation of Langerin⁺ DCs pTreg cells are converted only inefficiently despite antigen targeting through Langerin [52]. (F) IRF8-dependent DC1 are required for pTreg cell induction in the intestines in response to oral antigens, and such pTreg cell induction is compromised in mice with the genetic Irf8 deficiency in DCs that results in a decreased DC1:DC2 ratio [27].

Figure 2. Multiple immunomodulatory mechanisms that contribute to specific DC-induced T cell tolerance and conversion of pTreg cells

Programmed death ligand (PDL)1-PD1, B7H-ICOS, CD80/86-CTLA4/CD28, IL-2, IL-10, retinoic acid (RA), transforming growth factor (TGF)β, BTLA-HVEM, and CD5 have multiple direct or indirect roles in induction of T cell tolerance and promotion of pTreg cell differentiation including a transition of anergic T cells into pTreg cells by tolerogenic DCs [, , , , –, –103]. Such tolerogenic pathways may be possibly initiated by various specialized DCs within DC1 lineage.