Mitochondrial reactive oxygen species regulate the induction of CD8+ T cells by plasmacytoid dendritic cells

Oberkampf, Marine; Guillerey, Camille; Mouriès, Juliette; Rosenbaum, Pierre; Fayolle, Catherine; Bobard, Alexandre; Savina, Ariel; Ogier–Denis, Éric; Enninga, Jost; Amigorena, Sébastian; Leclerc, Claude; Dadaglio, Gilles

doi:10.1038/s41467-018-04686-8

Cited by 127 publications

(94 citation statements)

References 48 publications

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“…α-Glucans in Mycobacterium tuberculosis can induce ROS production and lead to DC maturation and lymphocyte proliferation, which is partly related to the induction of spleen tyrosine kinase (Syk) ( 132 ). The reduction in mitochondrial ROS production dramatically decreases the cross-presentation capacity of pDC and strongly impairs their ability to trigger CD8 + T cell responses ( 133 ). Mogilenko et al also report that reducing mitochondrial ROS production in DC ameliorates the disease in an IL-23-dependent model of psoriasis because of the reduction in IL-23 and skin inflammation ( 130 ).…”

Section: The Metabolism Modification Of Tol-dcmentioning

confidence: 99%

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

et al. 2020

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Over a half century, organ transplantation has become an effective method for the treatment of end-stage visceral diseases. Although the application of immunosuppressants (IS) minimizes the rate of allograft rejection, the common use of IS bring many adverse effects to transplant patients. Moreover, true transplant tolerance is very rare in clinical practice. Dendritic cells (DCs) are thought to be the most potent antigen-presenting cells, which makes a bridge between innate and adaptive immunity. Among their subsets, a small portion of DCs with immunoregulatory function was known as tolerogenic DC (Tol-DC). Previous reports demonstrated the ability of adoptively transferred Tol-DC to approach transplant tolerance in animal models. In this study, we summarized the properties, ex vivo generation, metabolism, and clinical attempts of Tol-DC. Tol-DC is expected to become a substitute for IS to enable patients to achieve immune tolerance in the future.

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Section: The Metabolism Modification Of Tol-dcmentioning

confidence: 99%

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

et al. 2020

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“…cDC1 development is dependent on several key transcriptional factors, such as BATF3, IRF8, ZBTB46, ID2, and ETV6 ( Aliberti et al, 2003 ; Hacker et al, 2003 ; Hildner et al, 2008 ; Meredith et al, 2012a , b ; Sichien et al, 2016 ; Lau et al, 2018 ). In addition to cDC1s, DCs derived under inflammatory conditions from hematopoietic progenitors or monocytes, and activated plasmacytoid DCs (pDCs), are also capable of cross-presentation ( Helft et al, 2015 ; Oberkampf et al, 2018 ). In general, cross-presentation of exogenous antigens can occur via two major pathways.…”

Section: Introductionmentioning

confidence: 99%

Thioesterase PPT1 balances viral resistance and efficient T cell crosspriming in dendritic cells

Wen

Liu

et al. 2019

Journal of Experimental Medicine

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Conventional type 1 dendritic cells (cDC1s) are inherently resistant to many viruses but, paradoxically, possess fewer acidic phagosomes that enable antigen retention and cross-presentation. We report that palmitoyl-protein thioesterase 1 (PPT1), which catabolizes lipid-modified proteins in neurons, is highly expressed in cDC1s. PPT1-deficient DCs are more susceptible to vesicular stomatitis virus (VSV) infection, and mice with PPT1 deficiency in cDC1s show impaired response to VSV. Conversely, PPT1-deficient cDC1s enhance the priming of naive CD8+ T cells into tissue-resident KLRG1+ effectors and memory T cells, resulting in rapid clearance of tumors and Listeria monocytogenes. Mechanistically, PPT1 protects steady state DCs from viruses by promoting antigen degradation and endosomal acidification via V-ATPase recruitment. After DC activation, immediate down-regulation of PPT1 is likely to facilitate efficient cross-presentation, production of costimulatory molecules and inflammatory cytokines. Thus, PPT1 acts as a molecular rheostat that allows cDC1s to crossprime efficiently without compromising viral resistance. These results suggest potential therapeutics to enhance cDC1-dependent crosspriming.

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“…Dendritic cells have specialized antigen presentation functions that are involved in activating T cell immunity, specifically CD4 + and CD8 + responses (4,36). Several recent studies have demonstrated mtROS, in particular H 2 O 2 regulates the induction of CD8 + T cells and the antigen presentation by plasmacytoid DCs to CD8 + T cells (29). These observations do not appear consistent with our findings, as we observed no alterations in the IAV-induced activation of both lung and splenic CD8 + and CD4 + T cell responses with MitoTEMPO treatment at the early and later stages of infection.…”

Section: Discussionmentioning

confidence: 99%

“…It appears that there is a high degree of redundancy in the mtROS-dependent activation of Ag cross-presentation (29). This is evident in studies that have utilized mtROS scavengers at different concentrations resulting in graded reductions in mtROS (29). For example, partial suppression of mtROS with S3QEL2, a mitochondrialtargeted antioxidant, had no effect on the cross-presentation capacity of pDC (29).…”

Section: Discussionmentioning

confidence: 99%

“…This is evident in studies that have utilized mtROS scavengers at different concentrations resulting in graded reductions in mtROS (29). For example, partial suppression of mtROS with S3QEL2, a mitochondrialtargeted antioxidant, had no effect on the cross-presentation capacity of pDC (29). However, only when there was an almost complete reduction in mtROS by S3QEL2 was there evidence for a reduction in pDC cross-presentation.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial Reactive Oxygen Species Contribute to Pathological Inflammation During Influenza A Virus Infection in Mice

Erlich

Liong

et al. 2020

Antioxidants & Redox Signaling

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Aims: Reactive oxygen species (ROS) are highly reactive molecules generated in different subcellular sites or compartments, including endosomes via the NOX2-containing nicotinamide adenine dinucleotide phosphate oxidase during an immune response and in mitochondria during cellular respiration. However, while endosomal NOX2 oxidase promotes innate inflammation to influenza A virus (IAV) infection, the role of mitochondrial ROS (mtROS) has not been comprehensively investigated in the context of viral infections in vivo. Results: In this study, we show that pharmacological inhibition of mtROS, with intranasal delivery of Mito-TEMPO, resulted in a reduction in airway/lung inflammation, neutrophil infiltration, viral titers, as well as overall morbidity and mortality in mice infected with IAV (Hkx31, H3N2). MitoTEMPO treatment also attenuated apoptotic and necrotic neutrophils and macrophages in airway and lung tissue. At an early phase of influenza infection, that is, day 3 there were significantly lower amounts of IL-1b protein in the airways, but substantially higher amounts of type I IFN-b following MitoTEMPO treatment. Importantly, blocking mtROS did not appear to alter the initiation of an adaptive immune response by lung dendritic cells, nor did it affect lung B and T cell populations that participate in humoral and cellular immunity. Innovation/Conclusion: Influenza virus infection promotes mtROS production, which drives innate immune inflammation and this exacerbates viral pathogenesis. This pathogenic cascade highlights the therapeutic potential of local mtROS antioxidant delivery to alleviate influenza virus pathology. Antioxid. Redox Signal. 32, 929-942.

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Mitochondrial reactive oxygen species regulate the induction of CD8+ T cells by plasmacytoid dendritic cells

Cited by 127 publications

References 48 publications

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

Thioesterase PPT1 balances viral resistance and efficient T cell crosspriming in dendritic cells

Mitochondrial Reactive Oxygen Species Contribute to Pathological Inflammation During Influenza A Virus Infection in Mice

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