CD81 Controls Immunity to <i>Listeria</i> Infection through Rac-Dependent Inhibition of Proinflammatory Mediator Release and Activation of Cytotoxic T Cells

Hoyo, Gloria Martı́nez del; Ramírez-Huesca, Marta; Levy, Shoshana; Boucheix, Claude; Rubinstein, Eric; Escalera, María Minguito de la; González-Cintado, Leticia; Ardavı́n, Carlos; Veiga, Esteban; Yáñez-Mó, Marı́a; Sánchez-Madrid, Francisco

doi:10.4049/jimmunol.1402957

Cited by 15 publications

(18 citation statements)

References 56 publications

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“…To ascertain the defective TLR-dependent inflammatory response in vivo due to the molecular association of MyD88-HDAC6, Hdac6 +/+ and Hdac6 -/- mice were intravenously injected with a lethal dose of Lm ( Fig 9F ) [ 44 ]. A protective effect against Lm -induced septic shock was observed from 3 to 10 days post-infection (dpi) ( Fig 9F ).…”

Section: Resultsmentioning

confidence: 99%

HDAC6 controls innate immune and autophagy responses to TLR-mediated signalling by the intracellular bacteria Listeria monocytogenes

et al. 2017

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Recent evidence on HDAC6 function underlines its role as a key protein in the innate immune response to viral infection. However, whether HDAC6 regulates innate immunity during bacterial infection remains unexplored. To assess the role of HDAC6 in the regulation of defence mechanisms against intracellular bacteria, we used the Listeria monocytogenes (Lm) infection model. Our data show that Hdac6-/- bone marrow-derived dendritic cells (BMDCs) have a higher bacterial load than Hdac6+/+ cells, correlating with weaker induction of IFN-related genes, pro-inflammatory cytokines and nitrite production after bacterial infection. Hdac6-/- BMDCs have a weakened phosphorylation of MAPK signalling in response to Lm infection, suggesting altered Toll-like receptor signalling (TLR). Compared with Hdac6+/+ counterparts, Hdac6-/- GM-CSF-derived and FLT3L-derived dendritic cells show weaker pro-inflammatory cytokine secretion in response to various TLR agonists. Moreover, HDAC6 associates with the TLR-adaptor molecule Myeloid differentiation primary response gene 88 (MyD88), and the absence of HDAC6 seems to diminish the NF-κB induction after TLR stimuli. Hdac6-/- mice display low serum levels of inflammatory cytokine IL-6 and correspondingly an increased survival to a systemic infection with Lm. The impaired bacterial clearance in the absence of HDAC6 appears to be caused by a defect in autophagy. Hence, Hdac6-/- BMDCs accumulate higher levels of the autophagy marker p62 and show defective phagosome-lysosome fusion. These data underline the important function of HDAC6 in dendritic cells not only in bacterial autophagy, but also in the proper activation of TLR signalling. These results thus demonstrate an important regulatory role for HDAC6 in the innate immune response to intracellular bacterial infection.

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Section: Resultsmentioning

confidence: 99%

HDAC6 controls innate immune and autophagy responses to TLR-mediated signalling by the intracellular bacteria Listeria monocytogenes

et al. 2017

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“…Wild type bone marrow cell suspensions were either cultured to obtain conventional DCs or both pDCs and cDCs as described 23, 24 . When indicated, OT-II CD4 T cells were cocultured with the corresponding subset of DCs (8:1T cell/DC ratio) in the presence or absence of chicken ovalbumin (OVA) 323–339 peptide.…”

Section: Methodsmentioning

confidence: 99%

miRNA profiling during antigen-dependent T cell activation: A role for miR-132-3p

Gutiérrez-Vázquez

Rodríguez-Galán

Fernández-Alfara

et al. 2017

Sci Rep

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microRNAs (miRNAs) are tightly regulated during T lymphocyte activation to enable the establishment of precise immune responses. Here, we analyzed the changes of the miRNA profiles of T cells in response to activation by cognate interaction with dendritic cells. We also studied mRNA targets common to miRNAs regulated in T cell activation. pik3r1 gene, which encodes the regulatory subunits of PI3K p50, p55 and p85, was identified as target of miRNAs upregulated after T cell activation. Using 3′UTR luciferase reporter-based and biochemical assays, we showed the inhibitory relationship between miR-132-3p upregulation and expression of the pik3r1 gene. Our results indicate that specific miRNAs whose expression is modulated during T cell activation might regulate PI3K signaling in T cells.

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“…Little is known regarding the contribution of CD81 to bacterial pathogenesis. Studies have shown that CD81 is required for the invasion (46) and infection (47) of Listeria monocytogenes. In the case of EPEC, CD81 does not seem to be required for bacterial colonization of cultured epithelial cells (not shown) or for F-actin clustering at infection sites (Fig.…”

Section: Discussionmentioning

confidence: 99%

EspH Suppresses Erk by Spatial Segregation from CD81 Tetraspanin Microdomains

et al. 2018

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Enteropathogenic (EPEC) belongs to a group of enteric human pathogens known as attaching-and-effacing (A/E) pathogens, which utilize a type III secretion system (T3SS) to translocate a battery of effector proteins from their own cytoplasm into host intestinal epithelial cells. Here we identified EspH to be an effector that prompts the recruitment of the tetraspanin CD81 to infection sites. EspH was also shown to be an effector that suppresses the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) signaling pathway at longer infection times. The inhibitory effect was abrogated upon deletion of the last 38 amino acids located at the C terminus of the protein. The efficacy of EspH-dependent Erk suppression was higher in CD81-deficient cells, suggesting that CD81 may act as a positive regulator of Erk, counteracting Erk suppression by EspH. EspH was found within CD81 microdomains soon after infection but was largely excluded from these domains at a later time. Based on our results, we propose a mechanism whereby CD81 is initially recruited to infection sites in response to EspH translocation. At a later stage, EspH moves out of the CD81 clusters to facilitate effective Erk inhibition. Moreover, EspH selectively inhibits the tumor necrosis factor alpha (TNF-α)-induced Erk signaling pathway. Since Erk and TNF-α have been implicated in innate immunity and cell survival, our studies suggest a novel mechanism by which EPEC suppresses these processes to promote its own colonization and survival in the infected gut.

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CD81 Controls Immunity to Listeria Infection through Rac-Dependent Inhibition of Proinflammatory Mediator Release and Activation of Cytotoxic T Cells

Cited by 15 publications

References 56 publications

HDAC6 controls innate immune and autophagy responses to TLR-mediated signalling by the intracellular bacteria Listeria monocytogenes

HDAC6 controls innate immune and autophagy responses to TLR-mediated signalling by the intracellular bacteria Listeria monocytogenes

miRNA profiling during antigen-dependent T cell activation: A role for miR-132-3p

EspH Suppresses Erk by Spatial Segregation from CD81 Tetraspanin Microdomains

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