Tolerogenicity is not an absolute property of a dendritic cell

Abstract

Pharmacological modulation is known to temper the immune capacity of DC, enhancing the notion that modulated Ag-bearing DC might be used therapeutically to induce tolerance. We have investigated phenotypic features shared by such DC, and queried their potential to tolerize in different settings. Immature, IL-10, TGF-b and 1a,25-dihydroxyvitamin D 3 -modulated BMDC all induced tolerance to male skin in female TCR transgenic A1.RAG mice, and the modulated DC also tolerized after exposure to the TLR4-ligand LPS. Transcript profiling revealed that this was achieved despite retaining much of the normal LPS-maturation response. No shared tolerance-associated transcripts could be identified. Equivalent BMDC could not tolerize in Marilyn TCR-transgenic mice. Simultaneous presentation of both A1.RAG and Marilyn peptide-Ag (Dby-H2E k and Dby-H2A b ) on immature (C57BL/6JxCBA/Ca) F1 BMDC also only achieved tolerance in A1.RAG mice. Both strains registered Ag, but Foxp3 1 Treg were only induced in A1.RAG mice. In contrast, Marilyn T cells showed greater proliferation and an inflammatory bias, in response to Ag presented by immature F1 BMDC in vitro. In summary, while pharmacological agents can skew DC to reinforce their immature tolerogenic phenotype, the outcome of presentation is ultimately an integrated response including T-cell-intrinsic components that can over-ride for immune activation.Key words: DC . TCR transgenic mice . Transplantation tolerance Supporting Information available online IntroductionDespite enthusiasm to exploit tolerogenic DC clinically [1][2][3], what constitutes a tolerogenic DC in vivo, and how it achieves tolerance, is still poorly understood. Immunological outcome was thought to be related directly to the maturation status of DC, with immature DC presenting for tolerance [4][5][6]; however, this simple view rapidly failed to account for accumulating experimental observations [7,8]. The functional diversity of DC has more recently been explained by the integration of multiple factors within a particular anatomical location causing the differentiation of appropriately tuned ''effector'' DC [9,10]. Although key co-inhibitory receptors, such as ILT3/4, PIR-B, PD-L1 and ICOSL, and immunoregulatory molecules, such as IDO and histone deacetylase HDAC11, have been variously implicated in driving tolerance [11][12][13][14][15][16], it is still not clear to what degree such molecules are universal players.A concern using immature DC in vivo is that they might become activated, particularly within the context of inflammation. If DC are to be used therapeutically, then the tolerant phenotype must be robust and stable. Numerous agents have been used to manipulate à These authors contributed equally to this study.Ãà These authors contributed equally to this study as senior authors. 1728DC in vitro to generate maturation-resistant cells for adoptive cell therapy [2,9]; however, attempts to induce tolerance to allografts in conventional models have generally failed unless combined with other immunosuppressive...

How Tolerogenic Dendritic Cells Induce Regulatory T Cells

“…Ex-vivo treatment of DCs with vitamin D receptor agonists elicits Treg-inducing tDC (114–122). Of note, vitamin D signaling appears to engage an autonomous transcriptional program in DCs that is distinct and independent from the transcriptional pathways that underlie DC maturation (123, 124).…”

The battle against immunopathology: infectious tolerance mediated by regulatory T cells

“…CCR9 + pDCs has been shown to induce Foxp3 + T regs and suppress antigen-specific immune responses both in vitro and in vivo [56]. Bone marrow-derived DCs preconditioned with TGF-β, IL-10, or vitamin D3 have also have been reported to induce tolerance in a skin graft model [57,58]. In humans and mice a subset of IL-10-producing DCs have been characterized in vivo , and were found to be potent inducers of Tr1 cell in vitro [59,60].…”

Th17 Cells Induce a Distinct Graft Rejection Response That Does Not Require IL-17A

“…Marilyn Th17 cells were found to generally produce higher levels of IFNγ compared to A1(M).RAG1 −/− both in vitro and after in vivo transfer. The dose of antigen has been shown to influence the level of IFNγ expression of Th17 cells (43) and the higher surface expression of the TCR by Marilyn compared to A1(M).RAG1 −/− T cells (54) may have a similar consequence.…”