Dendritic Cells Ameliorate Autoimmunity in the CNS by Controlling the Homeostasis of PD-1 Receptor+ Regulatory T Cells

Yogev, Nir; Frommer, Friederike; Lukas, Dominika; Kautz-Neu, Kordula; Karram, Khalad; Ielo, Daniele; Stebut, Esther von; Probst, Hans Christian; Broek, Maries van den; Riethmacher, Dieter; Birnberg, Tal; Blank, Thomas; Reizis, Boris; Korn, Thomas; Wiendl, Heinz; Jung, Steffen; Prinz, Marco; Kurschus, Florian C.; Waisman, Ari

doi:10.1016/j.immuni.2012.05.025

Cited by 184 publications

(203 citation statements)

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“…Moreover, in agreement with data reporting PD-L1 as necessary for the DC-mediated induction of Treg cells (24) and tolerance, our results indicate that HGF treatment significantly increases PD-L1 expression by DCs. Although these immunomodulating mechanisms may confer the regulatory properties of HGF-treated DCs, it does not provide the molecular mechanisms by which HGF generates tolerogenic DCs.…”

Section: Discussionsupporting

confidence: 92%

Hepatocyte Growth Factor Limits Autoimmune Neuroinflammation via Glucocorticoid-Induced Leucine Zipper Expression in Dendritic Cells

Benkhoucha

Molnarfi

Dunand-Sauthier

et al. 2014

The Journal of Immunology

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Autoimmune neuroinflammation, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), a prototype for T cell–mediated autoimmunity, is believed to result from immune tolerance dysfunction leading to demyelination and substantial neurodegeneration. We previously showed that CNS-restricted expression of hepatocyte growth factor (HGF), a potent neuroprotective factor, reduced CNS inflammation and clinical deficits associated with EAE. In this study, we demonstrate that systemic HGF treatment ameliorates EAE through the development of tolerogenic dendritic cells (DCs) with high expression levels of glucocorticoid-induced leucine zipper (GILZ), a transcriptional repressor of gene expression and a key endogenous regulator of the inflammatory response. RNA interference–directed neutralization of GILZ expression by DCs suppressed the induction of tolerance caused by HGF. Finally, adoptive transfer of HGF-treated DCs from wild-type but not GILZ gene–deficient mice potently mediated functional recovery in recipient mice with established EAE through effective modulation of autoaggressive T cell responses. Altogether, these results show that by inducing GILZ in DCs, HGF reproduces the mechanism of immune regulation induced by potent immunomodulatory factors such as IL-10, TGF-β1, and glucocorticoids and therefore that HGF therapy may have potential in the treatment of autoimmune dysfunctions.

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Section: Discussionsupporting

confidence: 92%

Hepatocyte Growth Factor Limits Autoimmune Neuroinflammation via Glucocorticoid-Induced Leucine Zipper Expression in Dendritic Cells

Benkhoucha

Molnarfi

Dunand-Sauthier

et al. 2014

The Journal of Immunology

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“…Another aspect that argues against a general interference with T cell responses by B7-H1 is the selective promoting effect of B7-H1-Ig on murine TGF-bmediated inducible T reg (iT reg ) differentiation, in line with other studies (30,45,46). However, it has been reported that induction of iT reg generation and function by B7-H1 is mediated via PD-1 (30,46). Hence although our data set provides clear evidence for the presence of a novel non-PD-1 receptor executing B7-H1 effects on T H 17 differentiation, other studies complementarily illustrate that under certain conditions such as presence of steadystate dendritic cells or under suboptimal stimulatory conditions, B7-H1-PD-1 interaction is also involved in the modulation of T cell differentiation.…”

Section: Discussionsupporting

confidence: 62%

“…This result was unexpected, because several studies proposed that this pathway primarily affects generation of IFN-g-producing T H 1 cells (41)(42)(43)(44). Another aspect that argues against a general interference with T cell responses by B7-H1 is the selective promoting effect of B7-H1-Ig on murine TGF-bmediated inducible T reg (iT reg ) differentiation, in line with other studies (30,45,46). However, it has been reported that induction of iT reg generation and function by B7-H1 is mediated via PD-1 (30,46).…”

Section: Discussionmentioning

confidence: 63%

B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non–PD-1–Mediated Pathway

Herold

Posevitz

Chudyka

et al. 2015

The Journal of Immunology

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It is currently acknowledged that TH17 cells are critically involved in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). In this article, we demonstrate that signals delivered by the coinhibitory molecule B7-homologue 1 (B7-H1) via a B7-homologue 1 mouse-IgG2aFc (B7-H1-Ig) fusion protein nearly abolish TH17, but not TH1 and TH2, differentiation via direct interaction with the T cell. These effects were equally pronounced in the absence of programmed death-1 or B7.1 and B7.2 on the T cell side, thus providing clear evidence that B7-H1 modulates T cell differentiation via a novel receptor. Mechanistically, B7-H1 interfered with early TCR-mediated signaling and cytokine-mediated induction of the TH17-determining transcription factors retinoic acid-related orphan receptor γ t and IFN regulator factor-4 in a programmed death-1 and B7-independent fashion. In an animal model of MS, active myelin oligodendrocyte glycoprotein–induced experimental autoimmune encephalomyelitis, B7-H1-Ig exhibited a significant and long-lasting effect on disease severity upon administration during the first 5 d of the priming phase, which was accompanied by reduced TH17 responses in the periphery and within the CNS. Importantly, B7-H1-Ig was even capable of interfering with T cell encephalitogenicity when interaction with the T cells occurred after priming using an adoptive transfer experimental autoimmune encephalomyelitis model. In line with this, both naive human CD4+ T cells and differentiated TH17 effector cells from MS patients were highly sensitive toward B7-H1-Ig–mediated TH17 suppression. Together, we propose the existence of a novel B7-H1–mediated immune-regulatory pathway in T cells, which selectively limits murine and human TH17 cell responses and might be therapeutically exploited to control TH17-mediated autoimmunity.

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“…45 Conversely, although the removal of cDCs and pDCs does not result in spontaneous autoimmunity, their removal results in the worsening of EAE and decreased levels of FoxP3 þ Tregs. 46 Taken together, these data suggest that DCs can control peripheral tolerance through their effects on the generation and maintenance of Treg populations under homeostatic and inflammatory conditions. Please note that although it has been postulated that specific DC populations promote the development of FoxP3 þ Tregs 38,40 and Tr1 43 cells in vivo, it is not yet clear whether these populations constitute specific tolerogenic DC lineages or represent alternative activation or maturation states of DCs.…”

Section: Role Of Dcs In the Peripheral Activation Of T Cellsmentioning

confidence: 86%

“…However, the transgenic expression of MHC class II in DCs is sufficient to recover the susceptibility to EAE of otherwise disease-resistant MHC class II-deficient mice. 50 It should also be noted that EAE can be induced in the absence of DCs, 46 indicating that although DCs are sufficient to induce CNS autoimmunity, other APCs can also promote the Figure 1 Classes of DCs. Two major classes of DCs have been identified based on their morphological and functional characteristics: conventional or classical DCs (cDCs) and plasmacytoid DCs (pDCs).…”

Section: Role Of Dcs In the Peripheral Activation Of T Cellsmentioning

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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Dendritic Cells Ameliorate Autoimmunity in the CNS by Controlling the Homeostasis of PD-1 Receptor+ Regulatory T Cells

Cited by 184 publications

References 50 publications

Hepatocyte Growth Factor Limits Autoimmune Neuroinflammation via Glucocorticoid-Induced Leucine Zipper Expression in Dendritic Cells

Hepatocyte Growth Factor Limits Autoimmune Neuroinflammation via Glucocorticoid-Induced Leucine Zipper Expression in Dendritic Cells

B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non–PD-1–Mediated Pathway

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

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