DC constitute a heterogeneous rather than a discrete cell population, that arises from CD34+ cells within the bone marrow (BM). They are found both in the thymus and secondary lymphoid tissue, in the circulation, in peripheral tissues such as skin, mucosal surfaces, intestine, lung, liver, and in maternal decidua. As APC, they are specialized in Ag capture, processing, and presentation; upon activation (as occurs following organ transplantation), they display enhanced capacity to migrate from the periphery via afferent lymph or blood to regional lymphoid tissues, where they interact with T cells and regulate their function.
Multiple DC subsets have been described in various tissues, especially the spleen [14
], since the first description of myeloid DC in mouse spleen by Steinman and Cohn in 1973/74 [16
]. In humans, the two major and intrinsically distinct subpopulations of DC are the “conventional” myeloid DC (mDC) and plasmacytoid DC (pDC). mDC and pDC are distinguished by both cell surface markers and function [18
]. Under inflammatory conditions, and following Toll-like receptor (TLR) ligation and Ag uptake (e.g. pathogen or donor alloAg), mDC migrate to T cell areas of secondary lymphoid tissue to initiate adaptive immunity. On the other hand, pDC that express a genetic profile more closely resembling lymphoid cell development [20
], recognize nucleic acids (both microbial and self) and produce interferon (IFN)-α, an important component of innate immune responses. Tolerogenic properties of both mDC and pDC (mouse and human) have been reported extensively, including the capacity of human mDC to induce Ag-specific tolerance in vivo, in healthy volunteers [21
Generally, human DC have been identified as major histocompatibility complex (MHC) class II+
) cells in peripheral tissues. In the circulation, they are lineage negative (Lin−
) and express blood DC Ags (BDCA); while mDC are Lin−
, pDC are Lin-/MHC II+
and Ig-like transcript 7+
. In mice, mDC are CD11c+
, whereas pDC are B220+
and express the murine pDC Ag-1/BM stromal cell Ag (BST)-2/CD317. Other mouse pDC markers include Siglec-H and the chemokine receptor CCR9. Based on their phenotypic and functional characteristics, DC can be identified at various stages of maturation, from immature through so-called `semi-mature' to mature. Immature DC express high endo-and phagocytic capacity, low levels of MHC class II and co-stimulatory molecules (CD40, CD80 and CD86), and low T cell stimulatory ability. These cells are associated with induction of T cell anergy and generation of Treg. By contrast, mature DC that express high levels of MHC class II, CD80 and CD86, have strong migratory capacity, associated with upregulation of the lymphoid homing receptor CCR7. They secrete the T helper (Th) 1 cell-driving cytokine IL-12. While in vitro, mature DC also expand Treg from naïve mice in the presence of IL-2, and increase their suppressive capacity [23
] and ability to suppress autoimmunity [24
], they also potently expand effector T cells.
Owing to their poor T cell stimulatory capacity, immature mDC have been considered the prototypic tolerogenic DC. The first reports to address the tolerogenic potential of immature DC (CD205+
, MHC II+
, and CD86dim
) in experimental (murine cardiac) allograft survival were by Fu et al [25
] and Lu L et al [26
]. In these studies, immature donor BM-derived mDC propagated in vitro in granulocyte-macrophage colony stimulating factor (GM-CSF) and administered 7 days before vascularized heart graft transplantation, significantly prolonged graft survival, either alone or in combination with co-stimulation blockade. Similar observations were reported by Lutz et al [27
], who showed that immature mDC, resistant to maturation, could prolong haplotype-specific heart allograft survival indefinitely (>100 days) also when given 7 days before transplantation. Subsequently, evidence accumulated that various phenotypically diverse DC could also promote transplant tolerance. Thus, semi-mature, maturation-resistant, `alternatively-activated' and genetically-modified DC have all been shown to prolong allograft survival and promote tolerance, often in conjunction with costimulation blockade, lymphocyte-depleting Abs or conventional immunosuppression [3
DC generated in vitro in the presence of tumor necrosis factor (TNF)-α, IL-10 + transforming growth factor beta (TGF-β) or dexamethasone, display a “semi-mature” phenotype, with intermediate levels of MHC II, CD40, CD80, and CD86 expression. These DC can markedly prolong organ allograft survival and inhibit graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation [28
]. “Semi-mature” DC, modulated by vitamin D3 and dexamethasone, can express the inhibitory molecules immunoglobulin (Ig)-like transcript – 3 (ILT3) and the B7 family member programmed death ligand – 1 (PDL-1= B7-H1) that plays a role in the induction of Treg [31
]. E-cadherin is an epithelial adhesion molecule that is also expressed by epidermal DC, i.e. Langerhans' cells (LC). Surface ligation of E-cadherin inhibits LC maturation [32
], whereas disruption of E-cadherin-mediated cell-cell contact by DC induces a “mature” phenotype with tolerogenic capacity. Such “mature” DC are able to induce CD4+
T cells that produce IL-10 instead of IFN-γ, and provide protection against induction of experimental autoimmune encephalitis [33
Apart from transplantation and autoimmunity, DC have been implicated in regulation of immune reactivity to the semi-allogeneic fetus. DC have been shown to be central to the control of immune tolerance at the maternal-decidual interface. In a study of the role of DC in maternal – fetal tolerance, bacterial lipopolysaccharide ( LPS) and IFN-α activation of human chorionic gonadotropin – treated, BM-derived and splenic DC, downregulated MHC II expression, but maintained high CD80 and CD86 expression, maintained high IL-12, but significantly increased IL-10 production [34
], suggesting mechanisms by which these DC might regulate immune reactivity directed against the fetus.
Thus, while the correlation between DC maturation and functional characteristics is well recognized, these data highlight the complexity of the relationship between DC phenotype and their tolerogenic potential.