Mapping the accumulation of co-infiltrating CNS dendritic cells and encephalitogenic T cells during EAE

Clarkson, Benjamin D.; Walker, Alec J.; Harris, Melissa G.; Rayasam, Aditya; Sándor, Mátyás; Fábry, Zsuzsanna

doi:10.1016/j.jneuroim.2014.09.016

Cited by 28 publications

(27 citation statements)

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“…The possibility was raised that NG2 null macrophages may exhibit less inflammatory properties than their WT counterparts [ 28 ], leading to a reduced ability to invade the CNS [ 30 ], and such a feature would support the lower extent of inflammation in NG2KO CNS during EAE. To determine if the possible role of NG2 in inflammation might also be relevant for other inflammatory cells that are liable to infiltrate the CNS during EAE [ 7 , 56 ], we sought to ascertain whether NG2 is expressed in WT mice or not by cells of the systemic immune system. We assessed the expression of NG2 by T cells in freshly isolated splenocytes and by bone-marrow-derived dendritic cells (BMDDCs) and macrophages (BMDMs).…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, it is likely that the skewing from Th1 to Th2 in MOG35-55-responsive NG2KO T cells is also related to a role of NG2 in DC activation. DCs are the main antigen-presenting cells in EAE [ 18 ], co-infiltrating the CNS with T cells [ 7 ]; their production of IL-12 is essential in the Th1-cell response implicated in the disease. IL-12 is a potent inducer of IFN-γ secretion by T cells; it drives the differentiation of naïve T cells to Th1 cells while impeding that to Th2 cells, and contributes to amplification and expansion of Th1 cells.…”

Section: Discussionmentioning

confidence: 99%

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NG2, a common denominator for neuroinflammation, blood–brain barrier alteration, and oligodendrocyte precursor response in EAE, plays a role in dendritic cell activation

et al. 2016

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In adult CNS, nerve/glial-antigen 2 (NG2) is expressed by oligodendrocyte progenitor cells (OPCs) and is an early marker of pericyte activation in pathological conditions. NG2 could, therefore, play a role in experimental autoimmune encephalomyelitis (EAE), a disease associated with increased blood–brain barrier (BBB) permeability, inflammatory infiltrates, and CNS damage. We induced EAE in NG2 knock-out (NG2KO) mice and used laser confocal microscopy immunofluorescence and morphometry to dissect the effect of NG2 KO on CNS pathology. NG2KO mice developed milder EAE than their wild-type (WT) counterparts, with less intense neuropathology associated with a significant improvement in BBB stability. In contrast to WT mice, OPC numbers did not change in NG2KO mice during EAE. Through FACS and confocal microscopy, we found that NG2 was also expressed by immune cells, including T cells, macrophages, and dendritic cells (DCs). Assessment of recall T cell responses to the encephalitogen by proliferation assays and ELISA showed that, while WT and NG2KO T cells proliferated equally to the encephalitogenic peptide MOG35-55, NG2KO T cells were skewed towards a Th2-type response. Because DCs could be responsible for this effect, we assessed their expression of IL-12 by PCR and intracellular FACS. IL-12-expressing CD11c+ cells were significantly decreased in MOG35-55-primed NG2KO lymph node cells. Importantly, in WT mice, the proportion of IL-12-expressing cells was significantly lower in CD11c+ NG2- cells than in CD11c+ NG2+ cells. To assess the relevance of NG2 at immune system and CNS levels, we induced EAE in bone-marrow chimeric mice, generated with WT recipients of NG2KO bone-marrow cells and vice versa. Regardless of their original phenotype, mice receiving NG2KO bone marrow developed milder EAE than those receiving WT bone marrow. Our data suggest that NG2 plays a role in EAE not only at CNS/BBB level, but also at immune response level, impacting on DC activation and thereby their stimulation of reactive T cells, through controlling IL-12 expression.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1563-z) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

NG2, a common denominator for neuroinflammation, blood–brain barrier alteration, and oligodendrocyte precursor response in EAE, plays a role in dendritic cell activation

et al. 2016

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“…Several studies from different laboratories suggest that CNS immune cells are activated before the appearance of clinical symptoms of MS and before T cell infiltration. For example, work from Dr. Fabry’s group demonstrated activation of microglia and CNS DCs ahead of the infiltration of MOG-specific T cells in the olfactory bulb ( 32 , 33 ), cerebellum, and along the white matter tracts ( 34 ). The activation of these cells was specific to EAE and was significantly increased compared to healthy mice and CFA-injected controls.…”

Section: Multiple Sclerosismentioning

confidence: 99%

“…However, a recent work using the developmental and functional criteria demonstrated that DCs develop from their precursors (pre-DCs) in the meninges and choroid plexus of mice ( 56 ). In the case of neuroinflammation due to injury or infection, the BBB gets compromised and peripheral DCs infiltrate the CNS ( 55 ), where they contribute to antigen presentation and reactivation of encephalitogenic T cells ( 34 , 57 ). Several studies also demonstrated the accumulation of DCs in white matter lesions and cerebrospinal fluid (CSF) of MS patients ( 58 , 59 ).…”

Section: Multiple Sclerosismentioning

confidence: 99%

NLR-Dependent Regulation of Inflammation in Multiple Sclerosis

et al. 2018

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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) associated with inappropriate activation of lymphocytes, hyperinflammatory responses, demyelination, and neuronal damage. In the past decade, a number of biological immunomodulators have been developed that suppress the peripheral immune responses and slow down the progression of the disease. However, once the inflammation of the CNS has commenced, it can cause serious permanent neuronal damage. Therefore, there is a need for developing novel therapeutic approaches that control and regulate inflammatory responses within the CNS. Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are intracellular regulators of inflammation expressed by many cell types within the CNS. They redirect multiple signaling pathways initiated by pathogens and molecules released by injured tissues. NLR family members include positive regulators of inflammation, such as NLRP3 and NLRC4 and anti-inflammatory NLRs, such as NLRX1 and NLRP12. They exert immunomodulatory effect at the level of peripheral immune responses, including antigen recognition and lymphocyte activation and differentiation. Also, NLRs regulate tissue inflammatory responses. Understanding the molecular mechanisms that are placed at the crossroad of innate and adaptive immune responses, such as NLR-dependent pathways, could lead to the discovery of new therapeutic targets. In this review, we provide a summary of the role of NLRs in the pathogenesis of MS. We also summarize how anti-inflammatory NLRs regulate the immune response within the CNS. Finally, we speculate the therapeutic potential of targeting NLRs in MS.

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“…However, this cellular population is largely, but not entirely, absent from the brain parenchyma in the steady state [18-24]. There is evidence that the minimal population of CNS resident DCs can be further augmented by additional DCs migrating into the brain during periods of inflammation [25, 26]. In contrast, macrophages (MΦs) in the perivascular spaces and microglia in the parenchyma are, at least numerically, the predominant APCs within the CNS.…”

Section: Introductionmentioning

confidence: 99%

Conditional silencing of H-2D^bclass I molecule expression on dendritic cells modulates the protective and pathogenic kinetics of virus-antigen specific CD8 T cell responses during Theiler’s Virus infection

Tritz

Orozco

Malo

et al. 2019

Preprint

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Theiler's murine encephalomyelitis virus (TMEV) infection of the central nervous systemis rapidly cleared in C57BL/6 mice by an anti-viral CD8 T cell response restricted by the MHC class I molecule, H-2D b . While the CD8 T cell response against neurotropic viruses is well characterized, the identity and function of the antigen presenting cell(s) involved in this process is(are) less well defined. To address this gap in knowledge, we developed a novel C57BL/6 H-2D b conditional knockout mouse that expresses an H-2D b transgene in which the transmembrane domain locus is flanked by LoxP sites. We crossed these H-2D b LoxP mice with MHC class I-deficient mice expressing Cre-recombinase under either the CD11c or LysM promoter in order to silence H-2D b restricted antigen presentation predominantly in dendritic cells or macrophages, respectively. Upon challenge with intracranial TMEV infection, we observe that CD11c+ APCs are critical for early priming of CD8 T cells against the immunodominant TMEV peptide VP2 121-130 presented in the context of the H-2D b molecule. This stands in stark contrast to later time points post TMEV infection where CD11c+ APCs appear dispensable for the activation of antigen-specific T cells; the functionality of these late-arising antiviral CD8 T cells is reflected in the restoration of viral control at later time points. These latearising CD8 T cells also retain their capacity to induce blood-brain barrier disruption. In contrast, when H-2D b restricted antigen presentation was selectively silenced in LysM+ APCs there was no overt impact on the priming of D b :VP2 121-130 epitope-specific CD8 T cells, although a modest reduction in immune cell entry into the CNS was observed. This work establishes a model system which enables critical dissection of MHC class I restricted antigen presentation to T cells, revealing cell specific and temporal features involved in the generation of antiviral CD8 T cell responses. Employing this novel system, we established CD11c+ cells as a pivotal driver of acute, but not later-arising, antiviral CD8 T cell responses against the TMEV immunodominant epitope VP2 121-130 , with functional implications both for T cell-mediated viral control and immunopathology. Class I conditional knockout mice were developed through construction of an H-2D b transgene, in which the transmembrane (TM) domain is flanked by LoxP sites. This transgene was introduced into C57BL/6 mice deficient in H-2D b and H-2K b , leaving the floxed D b as the onlyMHC class I molecule expressed by nucleated cells (Fig 1A) [33]. Crossing this transgenic mouse line with mice expressing Cre-recombinase under the CD11c, LysM, or CMV promoter, also on total MHC class I knockout backgrounds, allowed for CD11c+ cell specific, LysM+ cell specific, or ubiquitous ablation of MHC-I expression, respectively ( Fig 1B, Fig 1C, Fig 1D).Resultant mice will be referred to as CD11c D b conditional knockout (cKO), LysM D b cKO, CMV D b cKO, or Cre-littermates depending on whether the F1 generation pups inherited the...

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Mapping the accumulation of co-infiltrating CNS dendritic cells and encephalitogenic T cells during EAE

Cited by 28 publications

References 32 publications

NG2, a common denominator for neuroinflammation, blood–brain barrier alteration, and oligodendrocyte precursor response in EAE, plays a role in dendritic cell activation

NG2, a common denominator for neuroinflammation, blood–brain barrier alteration, and oligodendrocyte precursor response in EAE, plays a role in dendritic cell activation

NLR-Dependent Regulation of Inflammation in Multiple Sclerosis

Conditional silencing of H-2D^bclass I molecule expression on dendritic cells modulates the protective and pathogenic kinetics of virus-antigen specific CD8 T cell responses during Theiler’s Virus infection

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Mapping the accumulation of co-infiltrating CNS dendritic cells and encephalitogenic T cells during EAE

Cited by 28 publications

References 32 publications

NG2, a common denominator for neuroinflammation, blood–brain barrier alteration, and oligodendrocyte precursor response in EAE, plays a role in dendritic cell activation

NG2, a common denominator for neuroinflammation, blood–brain barrier alteration, and oligodendrocyte precursor response in EAE, plays a role in dendritic cell activation

NLR-Dependent Regulation of Inflammation in Multiple Sclerosis

Conditional silencing of H-2Dbclass I molecule expression on dendritic cells modulates the protective and pathogenic kinetics of virus-antigen specific CD8 T cell responses during Theiler’s Virus infection

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Product

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Conditional silencing of H-2D^bclass I molecule expression on dendritic cells modulates the protective and pathogenic kinetics of virus-antigen specific CD8 T cell responses during Theiler’s Virus infection