Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo

Hawiger, Daniel; Inaba, Kayo; Dorsett, Yair; Guo, Ming; Mahnke, Karsten; Rivera, Miguel N.; Ravetch, Jeffrey V.; Steinman, Ralph M.; Nussenzweig, Michel C.

doi:10.1084/jem.194.6.769

Cited by 1,645 publications

(1,695 citation statements)

References 58 publications

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“…Under normal, steady-state conditions, immature DCs cross-present antigens to induce peripheral tolerance [58]. Tolerance may be maintained at the level of T cell expansion through defective signaling pathways [59].…”

Section: Light Regulates Dcs At the Tumor Site To Promote Primingmentioning

confidence: 99%

Targeting tumors with LIGHT to generate metastasis-clearing immunity

Yü¹,

Fu²

2008

Cytokine & Growth Factor Reviews

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Metastastic diseases cause the majority of morbidity and mortality of cancer patients. Established tumors form both physical and immunological barriers to limit immune detection and destruction. Current immunotherapy of vaccination and adoptive transfer shows limited effect at least in part due to the existing barriers in the tumors and depending on the knowledge of tumor antigens. Tumor necrosis factor superfamily member 14 (TNFSF14) LIGHT interacts with stromal cells, dendritic cells, NK cells, naïve and activated T cells and tumor cells inside the tumor tissues via its two functional receptors, HVEM and lymphotoxin β receptor (LTβR). Targeting tumor tissues with LIGHT leads to augmentation of priming, recruitment, and retention of effector cells at tumor sites, directly or indirectly, to induce strong anti-tumor immunity to inhibit the growth of primary tumors as well as eradicate metastases. Intratumor treatment would break tumor barriers and allow strong immunity against various tumors without defining tumor antigens. This review summarizes recent findings to support that LIGHT is a promising candidate for an effective cancer immunotherapy.

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Section: Light Regulates Dcs At the Tumor Site To Promote Primingmentioning

confidence: 99%

Targeting tumors with LIGHT to generate metastasis-clearing immunity

Yü¹,

Fu²

2008

Cytokine & Growth Factor Reviews

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“…In the absence of antigen, T cells are in a non-activated state and do not exert effector functions, such as the secretion of cytokines. An antigen encounter can lead to the activation of specific T cells, however, the outcome of T cell activation is thought to depend critically on the APC type/subtype on which the antigen is presented [12][13][14]. For example, the production of IFN-γ by primed Th1 memory cells is regulated by the ability of APC to produce IL-12 [15,16].…”

Section: Introductionmentioning

confidence: 99%

The secretory IFN-γ response of single CD4 memory cells after activation on different antigen presenting cell types

Ott¹,

Tary‐Lehmann²,

Lehmann³

2007

Clinical Immunology

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It is unknown to what extent the heterogeneity of antigen presenting cells (APC) influences the IFN-γ response of CD4 memory cells. We restimulated DO11.10 T cell receptor (TCR)-transgenic cells and wild-type CD4 memory cells with OVA-peptide 323 -339 presented on purified dendritic cells (DC), macrophages, and B cells. Using IFN-γ ELISPOT assays we measured the number of cytokine producing T cells and the amount of cytokine produced by individual T cells at different time points after antigen encounter. The data showed that, when CD4 cells recognized antigen on DC, the induction of cytokine production was accelerated compared to macrophages and B cells. In contrast, the per-cell cytokine productivity was independent of the type of APC by which the T cells were restimulated. Moreover, the peptide concentration required for CD4 cell activation was comparable for the different APC. The data suggest that DC induce cytokine production in memory cells with accelerated activation kinetics, whereas 24 h of antigen stimulation on DC, macrophages, and B cells results in comparable levels of T cell activation. These data have implications for the understanding of T cell memory responses when T cells re-encounter antigen on different APC as well as for the monitoring of memory T cell responses ex vivo.

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“…Numerous studies linking tolerance to DC maturation status have emphasized the importance of incomplete signaling to T cells [4][5][6][7][8], while others have highlighted dominant interactions delivering negative or co-inhibitory signals as critical [11][12][13][14]16]. More complete explanations advocate some balance of the two, with micro-environmental context of antigenic encounter, and the nature of the Ag itself proposed as key determinants in establishing this balance of signaling [9,10].…”

Section: Discussionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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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Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo

Cited by 1,645 publications

References 58 publications

Targeting tumors with LIGHT to generate metastasis-clearing immunity

Targeting tumors with LIGHT to generate metastasis-clearing immunity

The secretory IFN-γ response of single CD4 memory cells after activation on different antigen presenting cell types

Tolerogenicity is not an absolute property of a dendritic cell

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