Lack of Conventional Dendritic Cells Is Compatible with Normal Development and T Cell Homeostasis, but Causes Myeloid Proliferative Syndrome

Birnberg, Tal; Bar-On, Liat; Sapoznikov, Anita; Caton, Michele L.; Cervantes-Barragán, Luisa; Makia, Divine; Krauthgamer, Rita; Brenner, Ori; Ludewig, Burkhard; Brockschnieder, Damian; Riethmacher, Dieter; Reizis, Boris; Jung, Steffen

doi:10.1016/j.immuni.2008.10.012

Cited by 202 publications

(307 citation statements)

References 74 publications

(101 reference statements)

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“…Our data add to these findings and demonstrate that DCs are crucial regulators of polyclonal Treg proliferation. However, some have also argued that DCs may be dispensable for Treg generation and maintenance, because Treg frequency is normal in CD11c-DTa mice that constitutively lack DCs (41). In contrast, a recent report demonstrated that acute depletion of DCs in vivo results in decreased Treg numbers and proliferation, which leads to an increase in T cells that are competent to produce inflammatory cytokines (25).…”

Section: Discussionmentioning

confidence: 99%

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Dendritic Cells Induce Regulatory T Cell Proliferation through Antigen-Dependent and -Independent Interactions

Zou

Caton

Koretzky

et al. 2010

The Journal of Immunology

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Section: Discussionmentioning

confidence: 99%

“…This apparent discrepancy may be explained by compensatory mechanisms that may be initiated in the constitutive absence of DCs, which allows a different cell type to substitute for DCs to maintain Treg homeostasis. Moreover, the physiologic proliferation of Tregs was not measured in the context of the constitutive absence of DCs (41).…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cells Induce Regulatory T Cell Proliferation through Antigen-Dependent and -Independent Interactions

Zou

Caton

Koretzky

et al. 2010

The Journal of Immunology

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“…Enhancing DC survival through transgenic expression of the baculoviral caspase inhibitor p35 or deletion of Fas leads to chronic lymphocyte activation and systemic autoimmunity (15,16), whereas increasing DC numbers by FMS-like tyrosine kinase 3 ligand (FLT3L) administration protects mice from autoimmunity via inducing regulatory T-cell (T reg ) accumulation (17)(18)(19). Conversely, constitutive ablation of cDCs through the expression of diphtheria toxin in CD11c + cells has been reported to cause fatal T-cell-mediated autoimmune disease (20) or a myeloid proliferative syndrome without obvious alterations of T-cell homeostasis (21). Mechanistically, peripheral DCs have been implicated in promoting homeostatic proliferation and survival of T cells (22)(23)(24) as well as inducing a low-level tonic signaling in naive T cells to program their responsiveness to foreign antigens (25).…”

mentioning

confidence: 99%

“…Mechanistically, peripheral DCs have been implicated in promoting homeostatic proliferation and survival of T cells (22)(23)(24) as well as inducing a low-level tonic signaling in naive T cells to program their responsiveness to foreign antigens (25). Moreover, although a direct role for DCs to promote T reg expansion and accumulation has been established by recent elegant studies (17,26), how this effect contributes to immune homeostasis is not fully understood (20,21,27,28). Because many of the previous studies have used nonphysiological approaches to modulate DC survival, how endogenous regulators of DC survival influence immune homeostasis and function remains to be established.…”

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confidence: 99%

Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function

Wang¹,

Huang²,

Vogel³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Homeostatic control of dendritic cell (DC) survival is crucial for adaptive immunity, but the molecular mechanism is not well defined. Moreover, how DCs influence immune homeostasis under steady state remains unclear. Combining DC-specific and -inducible deletion systems, we report that transforming growth factor betaactivated kinase 1 (TAK1) is an essential regulator of DC survival and immune system homeostasis and function. Deficiency of TAK1 in CD11c + cells induced markedly elevated apoptosis, leading to the depletion of DC populations, especially the CD8 + and CD103 + DC subsets in lymphoid and nonlymphoid tissues, respectively. TAK1 also contributed to DC development by promoting the generation of DC precursors. Prosurvival signals from Toll-like receptors, CD40 and receptor activator of nuclear factor-κB (RANK) are integrated by TAK1 in DCs, which in turn mediated activation of downstream NF-κB and AKT-Foxo pathways and established a gene-expression program. TAK1 deficiency in DCs caused a myeloid proliferative disorder characterized by expansion of neutrophils and inflammatory monocytes, disrupted T-cell homeostasis, and prevented effective T-cell priming and generation of regulatory T cells. Moreover, TAK1 signaling in DCs was required to prevent myeloid proliferation even in the absence of lymphocytes, indicating a previously unappreciated regulatory mechanism of DC-mediated control of myeloid cell-dependent inflammation. Therefore, TAK1 orchestrates a prosurvival checkpoint in DCs that affects the homeostasis and function of the immune system. innate immunity | immune tolerance

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“…However, the depletion of DCs does not affect thymic T-cell maturation and FoxP3 þ Treg generation, suggesting that the contribution of DCs to these processes is minimal. 34 Nevertheless, it is possible that DCs participate in the enforcement of tolerance to a specific subset of antigens or under specific conditions.…”

Section: Function Of Dcs In Cns Autoimmunitymentioning

confidence: 99%

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

2014

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Dendritic cells (DCs) are professional antigen-presenting cells that control the generation of adaptive immunity. Consequently, DCs have a central role in the induction of protective immunity to pathogens and also in the pathogenic immune response responsible for the development and progression of autoimmune disorders. Thus the study of the molecular pathways that control DC development and function is likely to result in new strategies for the therapeutic manipulation of the immune response. In this review, we discuss the role and therapeutic value of DCs in autoimmune diseases, with a special focus on multiple sclerosis. Cell Death and Differentiation (2015) 22, 215-224; doi:10.1038/cdd.2014; published online 29 August 2014 FactsDendritic cells (DCs) control central and peripheral tolerance through their effects on effector and regulatory T cells. Specific signaling pathways regulate the ability of different DC populations to promote effector and regulatory T-cell responses. Abnormalities in DC numbers, recruitment and function contribute to the pathology of multiple sclerosis (MS) and can be partially overcome by the use of disease-modifying therapies and the targeting of specific molecular pathways. Nanotechnology provides new tools for the modulation of DC activity in vivo and the therapeutic induction of antigenspecific tolerance in immune-mediated disorders. Open QuestionsAlthough DC populations that promote the development of forkhead box P3-positive (FoxP3 þ ) regulatory T cells (Tregs) have been identified, it is not yet clear whether these populations constitute separate tolerogenic DC lineages or represent alternative activation or maturation states of other DC populations. What are the different molecular pathways that control the DC's ability to prime effector or tolerogenic T-cell responses?There is an unmet clinical need for the development of methods for the efficient and consistent generation of tolerogenic DCs in vitro and in vivo that can be implemented in large-scale clinical setups.Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that control the activation and polarization of T cells into specific lineages and, consequently, the generation of antigen-specific antibody and T-cell responses. 1 In the context of an infectious challenge, the induction of pathogenspecific immune responses provides protective immunity to fight the infection. However, in the context of autoimmune diseases DCs regulate the balance between pathogenic and regulatory immune mechanisms, controlling disease onset and progression. Thus, DCs have a central role in the control of the adaptive immune response to pathogens and selftissues and therefore constitute potential targets for the therapeutic modulation of the immune response. In this review, we discus the role of DCs in autoimmune diseases, with a special emphasis on their role in the modulation of central nervous system (CNS) inflammation in MS. Received 12.6.14; accepted 23.6.14; Edited by H-U Simon; published online 29.8.14 Abbreviations: A...

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Lack of Conventional Dendritic Cells Is Compatible with Normal Development and T Cell Homeostasis, but Causes Myeloid Proliferative Syndrome

Cited by 202 publications

References 74 publications

Dendritic Cells Induce Regulatory T Cell Proliferation through Antigen-Dependent and -Independent Interactions

Dendritic Cells Induce Regulatory T Cell Proliferation through Antigen-Dependent and -Independent Interactions

Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

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