Dendritic Cells and Tolerance

Dendritic cell (DC) biology has recently shifted focus from the role that these uniquely well-equipped Ag-presenting cells play in the induction of immunity, to their pivotal role in immune tolerance (7,8). The tolerizing function of both classic myeloid DC (mDC) and more recently identified plasmacytoid DC (pDC) subsets has become apparent, as has the fact that both immature and mature DC can be tolerogenic. Moreover, the tolerizing properties of DCs appear to be linked to effects on Treg. Furthermore, the unique ability of DCs to capture and cross-present exogenous Ag on major histocompatibility complex (MHC) class I molecules can be used to induce Ag-specific CD8+ T-cell tolerance under noninflammatory conditions. Immature mDC above DCs, that express low surface levels of MHC class II and costimulatory molecules (CD40, CD80, CD86), can induce Ag-specific T-cell tolerance, whereas mature mDCs that express much higher levels of these molecules, induce T-cell immunity. This paradigm has been widely supported by data from experimental animal models, including observations that immature DCs of either donor or host origin can promote transplant tolerance induction. For example, one injection of immature, donor-derived DC, 7 d before organ transplant, extends (9) or prolongs indefinitely (10) mouse MHC-mismatched heart allograft survival in a donor-specific manner. This effect is markedly potentiated by blockade of the CD40-CD154 costimulatory pathway (11). 'Alternatively activated" or "regula-tory" DCs, that also exhibit very low costimulatory ability, can protect mice from lethal, acute graft-vs-host disease (12) and, if administered 7 d before transplant, prolong the survival of fully MHC-mismatched skin grafts (13). Similarly, heart allograft survival is prolonged significantly in rats when immature DC of host origin are given 1 d before transplantation (14). Moreover, impressive synergistic effects and indefinite (>100 d) donor-specific heart graft survival are achieved, when these immature DCs are combined with suboptimal immunosuppression (15).

Notably, there is also evidence that mature DCs can promote tolerance. In a cell culture system in which human monocyte-derived DCs cross-presented Ag to CD8+ T cells in the absence of CD4+ T-cell help, maturation of DCs with tumor necrosis factor (TNF)-a and prostaglandin E2 led to proliferation of T cells with tolerogenic properties (16). In separate studies using human autol-ogous DCs and T cells in the absence of Ag, mature but not immature DC induced CD4+ T cells expressing the transcriptional repressor Forkhead winged helix protein-3 (Foxp3) (Treg) that inhibited allogeneic mixed leukocyte reactions (17). In vivo, bone marrow-derived DCs matured with TNFa, but not lipopolysaccharide or anti-CD40 Ab, protected mice from CD4+ T cellmediated experimental autoimmune encephalomyelitis, despite strong expression of MHC class II and costimulatory molecules (18). It also is evident that immature or mature DC can prime Treg that prevent autoimmunity (19-21), as discussed below.

As the molecular basis of tolerance induction becomes better defined, it may become possible to use DCs derived from embryonic stem cells (22) to "repro-gram" the immune system to tolerate grafted therapeutic tissues derived from the same embryonic stem cell line.

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