Plasmacytoid dendritic cells: no longer an enigma and now key to transplant tolerance?

Abstract

Plasmacytoid (p) dendritic cells (DC) are a specialized subset of DC whose primary role was initially defined by the production of type I interferons in response to viral infection. They are now known to also possess a repertoire of functions capable of determining T cell fate and activation. Under homeostatic conditions, non-lymphoid tissue-resident pDC play a critical role in the regulation of mucosal immunity, as well as the development of central and peripheral tolerance. Although these cells display a number of characteristics that differ from conventional DC, particularly altered costimulatory molecule expression and poor allostimulatory capacity when interacting with T cells, this phenotype favors the generation of alloantigen-specific regulatory CD4(+) or CD8(+) T cells critical to the development of graft tolerance. In this minireview, we discuss pDC ontogeny, functional biology and the emerging data that demonstrate the importance of pDC in the induction of tolerance, as well as recent studies that define mechanisms underlying pDC-mediated tolerance to both solid organ and haematopoietic stem cell transplants. We also highlight their use in clinical settings and the potential of pDC both as targets and cellular therapeutic agents to improve the outcome of organ transplantation.

Figure 1. Phenotypic and functional characteristics of pDC

pDC respond to viral infection via recognition of viral nucleic acids by endosomal TLR7 and 9, activated (phosphorylated; P) IRF7-mediated production of type-1 IFN, cytotoxic molecules (granzyme B) and expression of cell differentiation markers (CD40, CD86, CCR7), and to bacterial infection by secretion of pro-inflammatory cytokines (TNFα; IL-6) mediated through TLR4. BM stromal cell Ag-2 (BST2; tetherin = CD137) is modulated by IFN responses through the ITAM-bearing signaling receptor Ig-like transcript (ILT) 7, in a negative feedback fashion. TSLP receptor expression, produced in response to TLR ligation, inhibits IL-17 production by T cells and promotes CD4⁺ Treg development. CCR9 (homing receptor)⁺ pDC in lymphoid tissue are potent inducers of Treg function, and can suppress Ag-specific immune responses. Surface-expressed PD-L1 (= B7-H1; CD274) and ICOS-L are also implicated in regulation of alloimmune cell responses, Treg development and suppression of alloreactive T cells. pDC also act as tolerogenic cells by expressing the inducible immunoregulatory enzyme IDO. cDC=conventional DC