Gatekeeper role of brain antigen‐presenting CD11c
            <sup>+</sup>
            cells in neuroinflammation

Paterka, Magdalena; Siffrin, Volker; Voß, Jan Oliver; Werr, Johannes; Hoppmann, Nicola; Gollan, René; Belikan, Patrick; Bruttger, Julia; Birkenstock, Jérôme; Jung, Steffen; Esplugues, Enric; Yogev, Nir; Flavell, Richard A.; Bopp, Tobias; Zipp, Frauke

doi:10.15252/embj.201591488

Cited by 44 publications

(51 citation statements)

References 57 publications

(88 reference statements)

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“…Our study shows that myelin-specific CD4 + T cells require ATGdependent phagocytosis in DCs to induce sustained inflammation and EAE development. CD11c + cells within the CNS alone, that is, in the absence of secondary lymphoid tissues, are sufficient to present antigen in vivo to primed myelin-reactive T cells to mediate CNS inflammation (8,9,39). In the steady state, CD11c + MHC class II + DCs within the CNS are enriched in the choroid plexus (40,41) which, along with the meningeal vasculature, is an active site for immune trafficking into and out of the CNS (42-44) and a first port of entry for pathogenic T cells during EAE (45).…”

Section: Discussionmentioning

confidence: 99%

“…Local reactivation and sustained accumulation of autoreactive T cells within the CNS are, therefore, considered instrumental in both MS and EAE. This effector phase can be modeled by adoptive transfer of primed myelin-specific CD4 + T cells into naïve mice (adoptive transfer EAE; AT-EAE) and depends on the presence of CD11c + antigen-presenting cells (APCs) (8,9). How myelin-reactive CD4 + T cells recognize their target organ and become reactivated to induce sustained CNS tissue damage are, however, incompletely understood.…”

mentioning

confidence: 99%

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ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4 ⁺ T cell pathogenicity during CNS inflammation

Keller

Sina

Kotur

et al. 2017

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

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Although reactivation and accumulation of autoreactive CD4 T cells within the CNS are considered to play a key role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), the mechanisms of how these cells recognize their target organ and induce sustained inflammation are incompletely understood. Here, we report that mice with conditional deletion of the essential autophagy protein ATG5 in classical dendritic cells (DCs), which are present at low frequencies in the nondiseased CNS, are completely resistant to EAE development following adoptive transfer of myelin-specific T cells and show substantially reduced in situ CD4 T cell accumulation during the effector phase of the disease. Endogenous myelin peptide presentation to CD4 T cells following phagocytosis of injured, phosphatidylserine-exposing oligodendroglial cells is abrogated in the absence of ATG5. Pharmacological inhibition of ATG-dependent phagocytosis by the cardiac glycoside neriifolin, an inhibitor of the Na, K-ATPase, delays the onset and reduces the clinical severity of EAE induced by myelin-specific CD4 T cells. These findings link phagocytosis of injured oligodendrocytes, a pathological hallmark of MS lesions and during EAE, with myelin antigen processing and T cell pathogenicity, and identify ATG-dependent phagocytosis in DCs as a key regulator in driving autoimmune CD4 T cell-mediated CNS damage.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4 ⁺ T cell pathogenicity during CNS inflammation

Keller

Sina

Kotur

et al. 2017

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

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“…First, intravital two-photon imaging of neuroinflammation in experimental autoimmune encephalomyelitis elucidated perivascular lymphocyte movement of CD4 + T cell subsets 86 and CD11c + cells 87 near vessels of the central nervous system. Second, intravital microscopy in a spinal injury model highlighted the role of Nr4a1, a regulator of macrophage catecholamine production, in leukocytes infiltration during disease exacerbation.…”

Section: Nervous System Interactionsmentioning

confidence: 99%

Multiparametric Imaging of Organ System Interfaces

Vandoorne

Nahrendorf

2017

Circ: Cardiovascular Imaging

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Cardiovascular diseases are a consequence of genetic and environmental risk factors that together generate arterial wall and cardiac pathologies. Blood vessels connect multiple systems throughout the entire body and allow organs to interact via circulating messengers. These same interactions facilitate nervous and metabolic system influence on cardiovascular health. Multiparametric imaging offers the opportunity to study these interfacing systems’ distinct processes, to quantify their interactions and to explore how these contribute to cardiovascular disease. Noninvasive multiparametric imaging techniques are emerging tools that can further our understanding of this complex and dynamic interplay. PET/MRI and multichannel optical imaging are particularly promising because they can simultaneously sample multiple biomarkers. Preclinical multiparametric diagnostics could help discover clinically relevant biomarker combinations pivotal for understanding cardiovascular disease. Interfacing systems important to cardiovascular disease include the immune, nervous and hematopoietic systems. These systems connect with ‘classical’ cardiovascular organs, like the heart and vasculature, and with the brain. The dynamic interplay between these systems and organs enables processes such as hemostasis, inflammation, angiogenesis, matrix remodeling, metabolism and fibrosis. As the opportunities provided by imaging expand, mapping interconnected systems will help us decipher the complexity of cardiovascular disease and monitor novel therapeutic strategies.

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“…Cell isolation during EAE. Brains, spinal cords, and spleens were removed, and immune cells were isolated as described previously (57). Naïve T-cell isolation.…”

Section: Creert2mentioning

confidence: 99%

Protein kinase CK2 governs the molecular decision between encephalitogenic T _H 17 cell and T _reg cell development

Ulges

Witsch

Pramanik

et al. 2016

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

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T helper 17 (TH17) cells represent a discrete TH cell subset instrumental in the immune response to extracellular bacteria and fungi. However, TH17 cells are considered to be detrimentally involved in autoimmune diseases like multiple sclerosis (MS). In contrast to TH17 cells, regulatory T (Treg) cells were shown to be pivotal in the maintenance of peripheral tolerance. Thus, the balance between Treg cells and TH17 cells determines the severity of a TH17 cell-driven disease and therefore is a promising target for treating autoimmune diseases. However, the molecular mechanisms controlling this balance are still unclear. Here, we report that pharmacological inhibition as well as genetic ablation of the protein kinase CK2 (CK2) ameliorates experimental autoimmune encephalomyelitis (EAE) severity and relapse incidence. Furthermore, CK2 inhibition or genetic ablation prevents TH17 cell development and promotes the generation of Treg cells. Molecularly, inhibition of CK2 leads to reduced STAT3 phosphorylation and strongly attenuated expression of the IL-23 receptor, IL-17, and GM-CSF. Thus, these results identify CK2 as a nodal point in TH17 cell development and suggest this kinase as a potential therapeutic target to treat TH17 cell-driven autoimmune responses.

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Gatekeeper role of brain antigen‐presenting CD11c ⁺ cells in neuroinflammation

Cited by 44 publications

References 57 publications

ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4 ⁺ T cell pathogenicity during CNS inflammation

ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4 ⁺ T cell pathogenicity during CNS inflammation

Multiparametric Imaging of Organ System Interfaces

Protein kinase CK2 governs the molecular decision between encephalitogenic T _H 17 cell and T _reg cell development

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Gatekeeper role of brain antigen‐presenting CD11c + cells in neuroinflammation

Cited by 44 publications

References 57 publications

ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4 + T cell pathogenicity during CNS inflammation

ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4 + T cell pathogenicity during CNS inflammation

Multiparametric Imaging of Organ System Interfaces

Protein kinase CK2 governs the molecular decision between encephalitogenic T H 17 cell and T reg cell development

Contact Info

Product

Resources

About

Gatekeeper role of brain antigen‐presenting CD11c ⁺ cells in neuroinflammation

ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4 ⁺ T cell pathogenicity during CNS inflammation

ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4 ⁺ T cell pathogenicity during CNS inflammation

Protein kinase CK2 governs the molecular decision between encephalitogenic T _H 17 cell and T _reg cell development