Plasmacytoid dendritic cells (PDCs) are key effectors in host innate immunity and orchestrate adaptive immune responses. CpG oligodeoxynucleotides (ODN) have potent immunostimulatory effects on PDCs through TLR9 recognition and signaling. Little is known about the effects of CpG ODN on human PDC-mediated T cell priming. Here we show that type B CpG ODN effectively promotes PDCs to prime allogeneic naive CD4+CD25− T cells to differentiate into CD4+CD25+ regulatory T (Treg) cells. The CD4+CD25+ T cells induced by CpG ODN-activated PDCs express forkhead transcription factor 3 and produce IL-10, TGF-β, IFN-γ, and IL-6, but low IL-2 and IL-4. These CD4+CD25+ T cells are hyporesponsive to secondary alloantigen stimulation and strongly inhibit proliferation of autologous or allogeneic naive CD4+ T cells in an Ag-nonspecific manner. CpG ODN-activated PDCs require direct contact with T cells to induce CD4+CD25+ Treg cells. Interestingly, IL-10 and TGF-β were undetectable in the supernatants of CpG ODN-stimulated PDC cultures. Both CpG-A and CpG-C ODN-activated PDCs similarly induced the generation of CD4+CD25+ Treg cells with strong immune suppressive function. This study demonstrates that TLR9 stimulation can promote PDC-mediated generation of CD4+CD25+ Treg cells and suggests PDCs may play an important role in the maintenance of immunological tolerance.
Human plasmacytoid dendritic cells (PDCs) can drive naive, allogeneic CD4+CD25− T cells to differentiate into CD4+CD25+Foxp3+ regulatory T cells (Tregs). However, the intracellular mechanism or mechanisms underlying PDC-induced Treg generation are unknown. In this study, we show that human PDCs express high levels of IDO, an intracellular enzyme that catabolizes tryptophan degradation. Triggering of TLR 9 with CpG oligodeoxynucleotides activates PDCs to up-regulate surface expression of B7 ligands and HLA-DR Ag, but also significantly increases the expression of IDO and results in the generation of inducible Tregs from CD4+CD25− T cells with potent suppressor cell function. Blocking IDO activity with the pharmacologic inhibitor 1-methyl-d-tryptophan significantly abrogates PDC-driven inducible Treg generation and suppressor cell function. Adding kynurenine, the immediate downstream metabolite of tryptophan, bypasses the 1-methyl-d-tryptophan effect and restores PDC-driven Treg generation. Our results demonstrate that the IDO pathway is essential for PDC-driven Treg generation from CD4+CD25− T cells and implicate the generation of kynurenine pathway metabolites as the critical mediator of this process.
IntroductionDendritic cells (DCs) are professional antigen-presenting cells (APCs) that display an extraordinary capacity to stimulate naive T cells and to initiate primary immune responses. 1 Recent studies suggest that DCs also play critical roles in the induction of peripheral immunologic tolerance, regulate the types of T-cell immune responses, and function as effector cells in innate immunity against microbes. 2,3 The diverse functions of DCs in immune regulation depend on the functional plasticity of DCs at the immature stage and the diversity of DC subsets and lineages. 2 Progress in understanding the molecular regulation of DC development from hematopoietic progenitor cells (HPCs) has led to the development of in vitro culture systems for the generation of large numbers of myeloid DCs from CD34 ϩ HPCs with granulocyte macrophage-colony-stimulating factor (GM-CSF) and tumor necrosis factor ␣ (TNF-␣) 4 or peripheral blood monocytes with GM-CSF and interleukin-4 (IL-4). 5,6 These culture systems not only permit detailed studies of DC biology, they allow the development of DC-based cancer vaccines. 7 Type 1 interferon-producing cells (IPCs), or plasmacytoid DC precursors, are distinct from myeloid-derived DC types. IPCs appear to be lymphoid-related because they express antigens or mRNA transcript related to lymphocytes (CD2, CD5, CD7, pre-Tcell receptor-␣ [TCR␣], immunoglobulin germline J chain, immunoglobulin-like 14.2, and Spi-B), and they display neither common myeloid antigens (CD11b, CD13, CD33) nor macrophage function or differentiation potential. IPCs express a set of microbial pattern recognition receptors (Toll-like receptors 7 and 9) different from that expressed by myeloid DCs (Toll-like receptors 2-6). 8 In antimicrobial innate immune responses, though monocytes or immature myeloid DCs play a critical role in phagocytoses of bacteria and parasites, IPCs play a major role in antiviral immunity by rapidly producing large amounts of type 1 interferon after viral infection. The critical role of IPCs in human antiviral immunity is suggested by the observation that the loss of IPCs correlates with disease progression to AIDS in HIV-infected patients. 9 In patients of systemic lupus erythematosus (SLE), constitutive activation of IPCs by dsDNA and anti-dsDNA antibody complexes appears to contribute to the pathogenesis of SLE. 10 In allogeneic bone marrow transplantation, increasing evidence indicates that IPCs may play an important role in immune responses after hematopoietic stem cell transplantation (HSCT) to facilitate engraftment and to prevent graft-versus-host disease (GVHD). [11][12][13] Understanding the molecular mechanisms underlying IPC development from HPCs may provide a novel therapy for viral [16][17][18][19][20] Studies also show that FLT3-L treatment increases the numbers of CD11c ϩ myeloid DCs and CD4 ϩ CD123 high CD11c Ϫ IPCs in the peripheral blood of human donors by 13-fold and 48-fold, respectively. 21,22 These findings suggest that FLT3-L directly induces the differentiation of C...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.