Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance

Abstract

Current organ transplantation therapy is life-saving but accompanied by well-recognized side effects due to post-transplantation systematic immunosuppressive treatment. Dendritic cells (DCs) are central instigators and regulators of transplantation immunity and are responsible for balancing allograft rejection and tolerance. They are derived from monocyte-macrophage DC progenitors originating in the bone marrow and are classified into different subsets based on their developmental, phenotypical, and functional criteria. Functionally, DCs instigate allograft immunity by presenting donor antigens to alloreactive T cells via direct, indirect, and semidirect recognition pathways and provide essential signaling for alloreactive T cell activation via costimulatory molecules and pro-inflammatory cytokines. Regulatory DCs (DCregs) are characterized by a relatively low expression of major histocompatibility complex, costimulatory molecules, and altered cytokine production and exert their regulatory function through T cell anergy, T cell deletion, and regulatory T cell induction. In rodent transplantation studies, DCreg-based therapy, by in situ targeting or infusion of ex vivo generated DCregs, exhibits promising potential as a natural, well-tolerated, organ-specific therapeutic strategy for promoting lasting organ-specific transplantation tolerance. Recent early-phase studies of DCregs have begun to examine the safety and efficacy of DCreg-induced allograft tolerance in living-donor renal or liver transplantations. The present review summarizes the basic characteristics, function, and translation of DCregs in transplantation tolerance induction.

Keywords: T cell; allograft; dendritic cell; tolerance; transplantation.

Figure 1

Origin and development of dendritic cells. With the exception of LCs, DCs develop from bone marrow-derived precursors. CDPs give rise to cDCs and pDCs. Monocytes differentiate into MoDCs in tissue as a consequence of inflammation or infection. LCs originate in prenatal precursor cells and are maintained locally by self-renewal under steady-state conditions. While under a severe inflammatory condition, LCs are replaced by blood-borne monocytes and acquire the capacity of self-renewal. DC, dendritic cell; LC, langerhans cells; CDP, common dendritic cell progenitor; cDC, classical dendritic cell; pDC, plasmacytoid dendritic cell; MoDC, monocyte-derived dendritic cell; YS-EMPs, Yolk sac-derived erythromyeloid progenitor cells; P-Sp/AGM para-aortic splanchnopleure/aorta, gonads, and mesonephros; HSC, hematopoietic stem cells; CMP, common myeloid progenitor cell; MP, myeloid progenitor cell; cMoP, common monocyte progenitor; GMP, granulocyte-macrophage progenitor; MDP, monocyte-macrophage DC progenitor.

Figure 2

Allorecognition pathways in transplantation. DCs instigate allograft immunity by presenting donor antigens to alloreactive T cells via direct, indirect, and semidirect recognition pathways. In the direct pathway, donor-derived DCs directly present intact donor (allogeneic) MHC molecules to alloreactive T cells. In the indirect pathway, host-derived DCs present donor-derived antigens, captured from damaged graft tissue or dying, donor-derived DCs, to alloreactive T cells. In the semidirect pathway, intact donor MHC molecules transferred to host DCs by cell-cell contact or extracellular vesicles are recognized. DC, dendritic cell; MHC, major histocompatibility complex; TCR, T-cell receptor.

Figure 3

Mechanisms of regulatory dendritic cells. DCregs exert a regulatory function through T cell anergy, T cell deletion, and regulatory T cell induction. These mechanisms involve direct cell–cell interactions through surface molecules, as well as through the immunosuppressive milieu via secretory factors. DCregs and Tregs interact with each other through a self-maintaining regulatory loop. DC, dendritic cell; PD-L1/2, programmed cell death ligand 1; ICOS-L, inducible T-cell costimulatory ligand; TGF-β, transforming growth factor β; HLA-G, human leukocyte antigen G; FasL, Fas ligand; ILT-2/3/4, immunoglobulin-like transcript-2/3/4; TRAIL, tumor necrosis factor-related apoptosis inducing ligand; BTLA, B- and T-lymphocyte attenuator; CCR7, C-C chemokine receptor 7; CXCR-4, C-X-C chemokine receptor type 4; IL, interleukin; RALDH, retinaldehyde dehydrogenases; NO, nitric oxide; ATP, adenosine triphosphate; ADP, adenosine diphosphate; AMP, adenosine monophosphate; IDO, indoleamine 2,3-dioxygenase; CO, carbon monoxide; HO-1, Heme oxygenase 1; Cox2, cyclooxygenase 2; PGES1, prostaglandin E synthase-1; ARG1, arginase 1; iNOS, inducible nitric oxide synthase; MHCII, major histocompatibility complex class II; PGE2, Prostaglandin E2; Tregs, regulatory T cells.

Figure 4

Manipulation of regulatory dendritic cells to promote transplantation tolerance. DCreg-based therapy is a promising strategy for establishing permanent, donor-specific immune tolerance and minimizing or even obviating the use of immunosuppressive drugs in transplantation. Manipulation of DCregs can be done by in situ targeting or infusion of ex vivo-generated DCregs or mediating donor-specific tolerance via alloreactive T cell anergy, T cell deletion, and Treg induction mechanisms. DCreg, regulatory dendritic cell; PSC, pluripotent stem cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-4, interleukin-4; PA, pharmacological agent; regulatory T cells.