Dendritic Cells: Versatile Players in Renal Transplantation

Abstract

Dendritic cells (DCs) induce and regulate adaptive immunity through migrating and maturing in the kidney. In this procedure, they can adopt different phenotypes-rejection-associated DCs promote acute or chronic injury renal grafts while tolerogenic DCs suppress the overwhelmed inflammation preventing damage to renal functionality. All the subsets interact with effector T cells and regulatory T cells (Tregs) stimulated by the ischemia-reperfusion procedure, although the classification corresponding to different effects remains controversial. Thus, in this review, we discuss the origin, maturation, and pathological effects of DCs in the kidney. Then we summarize the roles of divergent DCs in renal transplantation: taking both positive and negative stages in ischemia-reperfusion injury (IRI), switching phenotypes to induce acute or chronic rejection, and orchestrating surface markers for allograft tolerance via alterations in metabolism. In conclusion, we prospect that multidimensional transcriptomic analysis will revolute researches on renal transplantation by addressing the elusive mononuclear phagocyte classification and providing a holistic view of DC ontogeny and subpopulations.

Keywords: dendritic cells; ischemic–reperfusion injury; rejection; renal transplantation; tolerance.

Figure 1

DCs in the kidney originate from bone hematopoietic stem cells and involve in lymphatic recycling in vivo. When ischemia–reperfusion occurs, immature DCs start to search for interactions with T lymphocytes and change their surface proteins including CCR2, CCR5 to induce tolerance procedure (expressing PD-L1/2 and CD80/86) or rejection procedure (expressing CCR7 and MHC class II). The activation can be derived from pathogen-associated molecular patterns and danger-associated molecular patterns in the procedure of ischemia-reperfusion.

Figure 2

Immature DCs can be activated by antigens derived from ischemia-reperfusion and act as the role of powerful antigen-presenting cells to trigger antibody-mediated rejection and cell-mediated rejection. The result of antibody-mediated rejection is activated B cell releasing harmful antibodies while active cytotoxic T cells kill donor cells forming cell-mediated rejection. On the contrary, when treated by specific drugs, immature DCs can also maintain their surface markers to suppress possible inflammation caused by transplantations via signal pathways activation regulating metabolism alterations. The signal pathways include NF-κB and mTOR summarized in the section The Generation of Tolerogenic DCs. The metabolism alterations involve glycometabolism and lipid metabolism with more details in the section The Generation of Tolerogenic DCs.

Figure 3

In response to specific factors including DAMPs, recipient cDCs and pDCs change into recipient rejection-related DCs. If rapamycin, IL-10, Vit D, or a low dose of GM-CSF is employed to treat recipient rejection-related DCs, recipient tolerogenic DCs can be generated. Under the control of recipient rejection-related DCs, naive T cells differentiate to CD8⁺ T cells with the help of IL-2 and differentiate to CD4⁺ T cells assisted by IL-6 and IL-4. Memory T cells (Tm cells) also originate from naïve T cells, and this alteration is associated with IL-2 and IL-15. Treg cells can occur when IL-10 and TGF-β are secreted by recipient rejection-related DCs. Besides, tolerogenic DCs reduce CD4⁺ T cell activation, and they can impair active CD8⁺ T cells. Furthermore, Tm cells tend to be anti-inflammatory promoted by tolerogenic DCs. Treg cells survive for a longer period with tolerogenic DCs than with rejection-related DCs.

Figure 4

Tolerogenic DCs are usually generated via specific substances. These stimulations derived from cytokines (IL-10, TGF-β), immunosuppressants (Rapamycin, Dexamethasone), and others (PEG2, DAMPs) mediate signal pathways involving NF-κB and mTOR activation, causing surface protein expression alterations (highly expressing PD-L1/2, CD80/86, FasL C1QBP while decreasing MHC expression) and metabolism changes (from glucose to pynuvate). All these procedures happen in the donor kidney and the immune organs including the thymus, spleen, lymph node, and bone marrow.