Differentiation Stages and Subsets of Tolerogenic Dendritic Cells

Lutz, Manfred B.

doi:10.1002/9783527619696.ch26

Cited by 7 publications

(12 citation statements)

References 196 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data also show that the modulatory effect of T reg is not functional after a combined LPS ϩ CD40 maturation, further extending our findings that the quality of DC maturation heavily influences T cell activation and differentiation (34). Endogenous inflammatory signals such as TNF, TLR ligands such as LPS, or CD40 ligation can result in DC maturation although the stage or quality of maturation are substantially different especially with respect to their cytokine production (35,36).…”

Section: Discussionsupporting

confidence: 77%

Suppression of Mature Dendritic Cell Function by Regulatory T Cells In Vivo Is Abrogated by CD40 Licensing

Hänig

Lutz

2008

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The priming of CD4+ effector T cells (Teff) in vivo is induced by mature dendritic cells (DC) and controlled by CD4+CD25+Foxp3+ regulatory T cells (Treg). It remains unclear,however, how Teff priming vs Treg suppression are regulated during Ag presentation by DC in secondary lymphoid organs at the simultaneous presence of Teff and Treg. In this study, we used an peptide-specific DO11.10 TCR-transgenic adoptive transfer model to follow the Teff priming kinetics and the mechanisms of suppression by Treg. Treg activation was slower as compared with Teff and could not influence the early Teff expansion but limited the Teff response leading to lower Teff numbers in the memory phase. DC-Treg cell contacts remained unaltered during suppression by Treg and led to a down-regulation of the costimulatory molecules CD80, CD86, PD-L1, and PD-L2 but not MHC II, CD40, ICOS-L, or CD70 from the mature DC surface. This effect was observed only after DC maturation with TNF or LPS but not after additional CD40 licensing. Together, our data indicate that Treg suppression against nonself Ags in vivo occurs delayed due to the slower Treg response, is mediated to a large extent through DC modulation, but is controlled by the type of DC maturation.

show abstract

Section: Discussionsupporting

confidence: 77%

Suppression of Mature Dendritic Cell Function by Regulatory T Cells In Vivo Is Abrogated by CD40 Licensing

Hänig

Lutz

2008

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Tolerogenicity of DCs is an intrinsic functional definition for this cell type and their induction of T cell anergy, regulatory T cells and T cell deletion have been reported ( 1 ). All major DC subsets have been described to exert tolerogenic functions.…”

Section: Tolerogenic Dendritic Cells (Dcs)mentioning

confidence: 99%

“…Thus, maturation resistance was considered as a hallmark of tolerogenic DCs to maintain their immaturity. Several protocols have been developed to achieve maturation resistance, mostly using maturation inhibitors such as IL-10, TGF-β, dexamethasone, or vitamin D3 alone or in combinations ( 1 ). Reports on the transcriptional profiling of such DCs treated with tolerogenic substances followed and have been described elsewhere ( 9 , 10 ).…”

Section: Tolerogenic Dendritic Cells (Dcs)mentioning

confidence: 99%

Tolerogenic Transcriptional Signatures of Steady-State and Pathogen-Induced Dendritic Cells

et al. 2018

Self Cite

View full text Add to dashboard Cite

Dendritic cells (DCs) are key directors of tolerogenic and immunogenic immune responses. During the steady state, DCs maintain T cell tolerance to self-antigens by multiple mechanisms including inducing anergy, deletion, and Treg activity. All of these mechanisms help to prevent autoimmune diseases or other hyperreactivities. Different DC subsets contribute to pathogen recognition by expression of different subsets of pattern recognition receptors, including Toll-like receptors or C-type lectins. In addition to the triggering of immune responses in infected hosts, most pathogens have evolved mechanisms for evasion of targeted responses. One such strategy is characterized by adopting the host’s T cell tolerance mechanisms. Understanding these tolerogenic mechanisms is of utmost importance for therapeutic approaches to treat immune pathologies, tumors and infections. Transcriptional profiling has developed into a potent tool for DC subset identification. Here, we review and compile pathogen-induced tolerogenic transcriptional signatures from mRNA profiling data of currently available bacterial- or helminth-induced transcriptional signatures. We compare them with signatures of tolerogenic steady-state DC subtypes to identify common and divergent strategies of pathogen induced immune evasion. Candidate molecules are discussed in detail. Our analysis provides further insights into tolerogenic DC signatures and their exploitation by different pathogens.

show abstract

“…Several in vitro methods have been developed in order to generate tolerogenic DCs [5]. Additionally, a growing body of experimental data highlights the role of Treg cells in maintaining tolerance through the suppression of DC immunostimulatory capacity [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…These tolerogenic DCs show decreased expression of costimulatory molecules such as CD80 and CD86 and reduced production of proinflammatory cytokines . Several in vitro methods have been developed in order to generate tolerogenic DCs . Additionally, a growing body of experimental data highlights the role of Treg cells in maintaining tolerance through the suppression of DC immunostimulatory capacity .…”

Section: Introductionmentioning

confidence: 99%

Cell‐extrinsic CTLA4‐mediated regulation of dendritic cell maturation depends on STAT3

2014

View full text Add to dashboard Cite

Regulatory T (Treg) cells suppress immune responses by downregulating the expression of costimulatory molecules CD80 and CD86 on dendritic cells (DCs) through cytotoxic T lymphocyte antigen 4 (CTLA4). However, it is unclear whether inducible Treg (iTreg) cellscan hamper immune responses via the same mechanism. Moreover, whether a reverse signal sent by CTLA4 alone is sufficient to prevent maturation of DCs has never been evaluated. Here, we demonstrate that stimulation of DCs with CTLA4, either expressed by inducible Treg cells or by cross-linking with CTLA4Fc fusion protein, can significantly inhibit LPS-induced CD80 and CD86 mRNA and protein expression in both mouse and human DCs. Importantly, CTLA4Fc-treated DCs had reduced ability to stimulate CD4 + and CD8 + T-cell proliferation and cytokine production in both syngeneic and allogeneic settings. We also investigated the molecular mechanism involved in the induction of tolerogenic DCs by CTLA4. We determined that the interaction of CTLA4 with its high affinity ligand CD80 on DCs induces STAT3 phosphorylation followed by reduction of NF-κB activity, leading to suppression of CD80 and CD86 gene transcription and protein production. Our work opens new windows for the generation of tolerogenic DCs that could ultimately be used for treating autoimmune diseases and transplant rejection. Keywords: Dendritic cells r Immune regulation r Regulatory T cells r ToleranceAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDendritic cells (DCs) play a central role in the initiation and regulation of immune responses [1]. Although traditionally viewed as immunity inducers, in the absence of inflammatory danger signals, DCs participate in the maintenance of peripheral tolerance [2] and can induce T-cell deletion, anergy and generation and expansion of regulatory T (Treg) cells [3]. These tolerogenic DCs show decreased expression of costimulatory molecules such as CD80Correspondence: Dr. Li Zhang e-mail: lzhang@uhnres.utoronto.ca and CD86 and reduced production of proinflammatory cytokines [4]. Several in vitro methods have been developed in order to generate tolerogenic DCs [5]. Additionally, a growing body of experimental data highlights the role of Treg cells in maintaining tolerance through the suppression of DC immunostimulatory capacity [6][7][8][9]. However, the molecular mechanisms by which Treg cells modulate DC function remain obscure. Elucidation of the mechanisms governing DC maturation may facilitate their use in treating a variety of immune-related conditions including autoimmune diseases and transplantation.CD4 + CD25 + Foxp3 + Treg cells play a pivotal role in maintaining self-tolerance and preventing autoimmunity. At least two major subtypes of CD4 + CD25 + Foxp3 + Treg cells have been identified: Thymus-derived natural T regulatory (nTreg) cells and C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu1144 Aleksandra Kowalczyk et al. Eur. J. Immunol. 2014. 44: 1143-1155 ...

show abstract

Differentiation Stages and Subsets of Tolerogenic Dendritic Cells

Cited by 7 publications

References 196 publications

Suppression of Mature Dendritic Cell Function by Regulatory T Cells In Vivo Is Abrogated by CD40 Licensing

Suppression of Mature Dendritic Cell Function by Regulatory T Cells In Vivo Is Abrogated by CD40 Licensing

Tolerogenic Transcriptional Signatures of Steady-State and Pathogen-Induced Dendritic Cells

Cell‐extrinsic CTLA4‐mediated regulation of dendritic cell maturation depends on STAT3

Contact Info

Product

Resources

About