Induction of Regulatory T Cells and Dominant Tolerance by Dendritic Cells Incapable of Full Activation

Yates, Stephen F.; Paterson, Alison M.; Nolan, Kathleen F.; Cobbold, Stephen; Saunders, Nigel J.; Waldmann, Herman; Fairchild, Paul J.

doi:10.4049/jimmunol.179.2.967

Cited by 86 publications

(78 citation statements)

References 44 publications

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“…As for BMDC-VD3 [17], surface expression of co-stimulatory molecules CD40 and CD86 was indistinguishable between the cytokinemodulated and untreated immature BMDC, with levels of MHC class II slightly down-modulated (Supporting Information Fig. 3).…”

Section: Searching For Molecular Patterns That Correlate With DC Tolementioning

confidence: 89%

“…Having demonstrated that BMDC-VD3 can induce tolerance in A1.RAG mice [17], we now asked if BMDC influenced by the immunomodulatory cytokines IL-10 (BMDC-IL10) and TGF-b (BMDC-TGF) could do the same. Both of the cytokine-modulated populations induced long-term transplantation tolerance even after LPS maturation ( Fig.…”

Section: Exposed To Different Biological Modifiers Induce Tolerancmentioning

confidence: 99%

“…Adoptive transfer of BMDC and skin grafting were performed as described previously [17]. For Ab-induced tolerance, 1 mg of non-depleting anti-CD4 (YTS177.9.6) or IgG2a isotype control Ab was administered as a single dose on the day of grafting [26].…”

Section: Tolerance Induction and Skin Graftingmentioning

confidence: 99%

“…Numerous agents have been used to manipulate DC 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 agents [1], necessitating a move to reductionist models. We previously showed that we could induce tolerance to male skin grafts in female TCR transgenic A1.RAG mice by transferring either ''immature'' BMDC or BMDC modulated using 1a, 25-dihydroxyvitamin D 3 , (BMDC-VD3), but only the modulated cells retained their capacity to induce tolerance after maturation with the TLR4-ligand LPS [17]. The tolerance induced was long-lasting, dominant and associated with de novo generation of peripheral Foxp3 1 T cells.…”

Section: Introductionmentioning

confidence: 99%

“…We previously showed that we could induce tolerance to male skin grafts in female TCR transgenic A1.RAG mice by transferring either ''immature'' BMDC or BMDC modulated using 1a, 25-dihydroxyvitamin D 3 , (BMDC-VD3), but only the modulated cells retained their capacity to induce tolerance after maturation with the TLR4-ligand LPS [17]. The tolerance induced was long-lasting, dominant and associated with de novo generation of peripheral Foxp3 1 T cells.…”

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confidence: 99%

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Tolerogenicity is not an absolute property of a dendritic cell

et al. 2010

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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 Ã These authors contributed equally to this study.ÃÃ 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...

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Section: Searching For Molecular Patterns That Correlate With DC Tolementioning

confidence: 89%

Section: Exposed To Different Biological Modifiers Induce Tolerancmentioning

confidence: 99%

Section: Tolerance Induction and Skin Graftingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Tolerogenicity is not an absolute property of a dendritic cell

et al. 2010

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Particulate‐Based Single‐Dose Local Immunosuppressive Regimen for Inducing Tolerogenic Dendritic Cells in Xenogeneic Islet Transplantation

Pathak

Acharya

Regmi

et al. 2020

Adv Healthcare Materials

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Recent studies emphasize on developing immune tolerance by an interim administration of various immunosuppressive drugs. In this study, a robust protocol is reported for local immunomodulation using a single‐dose of FK506 microspheres and clodronate liposomes (mFK+CLO) in a xenogeneic model of islet transplantation. Surprisingly, the single‐dose treatment with mFK+CLO induce tolerance to the islet xenograft. The recipient mice display tolerogenic dendritic cells (tDCs) with decreased antigen presenting ability and T cell activation capacity. Furthermore, a reduced percentage of CD4+ and CD8+ T cells and an impaired differentiation of naïve CD4+ T cells into interferon‐γ producing Th1 and interleukin‐17 producing Th17 cells are observed. In addition, the immunosuppressive protocol leads to the generation of Foxp3+ regulatory T cells (Tregs) which are required for the long‐term graft survival. The enhanced generation of tDCs and Tregs by the single treatment of mFK+CLO cause xenograft tolerance, suggesting a possible clinical strategy which may pave the way towards improving therapeutic outcomes of clinical islet transplantation.

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Biomaterials as vaccine adjuvants

Jones

2008

Biotechnology Progress

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Biomaterials are promising candidate adjuvants to enhance vaccine efficacy. Through adjuvant design, we can broaden the use of vaccines to diseases such as AIDS, malaria, and cancer. This review addresses the fundamentals of vaccine and adjuvant function in order to determine guidelines for adjuvant design, including aspects of the vaccine such as disease target, antigen formulation, and delivery route. An ideal biomaterial adjuvant will perform three functions. (1) It will deliver the antigen selectively to dendritic cells. This has been accomplished through release of chemokines or cytokines, use of antidendritic cell antibodies, and even through particle size selection. (2) It will activate the dendritic cells, improving antigen presentation. Biomaterials themselves have been shown to activate innate immunity, but specific innate‐activating ligands have also been included in adjuvant formulations. Finally, (3) it will release the antigen appropriately into the dendritic cell. Tuning release to be pH sensitive and engineering endosomal release are strategies that have been used. There is a real opportunity to rationally design better biomaterial adjuvants that will significantly expand and improve vaccine function.

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Induction of Regulatory T Cells and Dominant Tolerance by Dendritic Cells Incapable of Full Activation

Cited by 86 publications

References 44 publications

Tolerogenicity is not an absolute property of a dendritic cell

Tolerogenicity is not an absolute property of a dendritic cell

Particulate‐Based Single‐Dose Local Immunosuppressive Regimen for Inducing Tolerogenic Dendritic Cells in Xenogeneic Islet Transplantation

Biomaterials as vaccine adjuvants

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