Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation

Torchinsky, Miriam Beer; Garaude, Johan; Martín, Andrea P.; Blander, J. Magarian

doi:10.1038/nature07781

Cited by 312 publications

(303 citation statements)

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“…cDC may also favor Th17 differentiation during the elimination of infected apoptotic cells (33). This requires both TLR triggering and TGF-b synthesis because of apoptotic cell uptake (33). Again, pDC and cDC demonstrated distinct properties because we demonstrated that TLR triggering associated with TGF-b limit Th17 commitment.…”

Section: Discussionmentioning

confidence: 77%

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TGF-β–Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

Bonnefoy

Couturier

Clauzon

et al. 2011

The Journal of Immunology

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TGF-β is required for both Foxp3+ regulatory T cell (Treg) and Th17 commitment. Plasmacytoid DCs (pDC) have been shown to participate to both Treg and Th17 commitment as well. However, few studies have evaluated the direct effect of TGF-β on pDC, and to our knowledge, no study has assessed the capacity of TGF-β–exposed pDC to polarize naive CD4+ T cells. In this paper, we show that TGF-β–treated pDC favor Th17 but not Treg commitment. This process involves a TGF-β/Smad signal, because TGF-β treatment induced Smad2 phosphorylation in pDC and blockade of TGF-β signaling with the SD208 TGF-βRI kinase inhibitor abrogated Th17 commitment induced by TGF-β–treated pDC. Moreover, TGF-β mRNA synthesis and active TGF-β release were induced in TGF-β–treated pDC and anti–TGF-β Ab blocked Th17 commitment. Unexpectedly, TGF-β treatment also induced increased IL-6 production by pDC, which serves as the other arm for Th17 commitment driven by TGF-β–exposed pDC, because elimination of IL-6–mediated signal with either IL-6– or IL-6Rα–specific Abs prevented Th17 commitment. The in vivo pathogenic role of TGF-β–treated pDC was further confirmed in the Th17-dependent collagen-induced arthritis model in which TGF-β–treated pDC injection significantly increased arthritis severity and pathogenic Th17 cell accumulation in the draining lymph nodes. Thus, our data reveal a previously unrecognized effect of TGF-β–rich environment on pDC ability to trigger Th17 commitment. Such findings have implications in the pathogenesis of autoimmune diseases or immune responses against mucosal extracellular pathogens.

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Section: Discussionmentioning

confidence: 77%

“…Indeed, when exposed to TGF-b, cDC have been demonstrated to harbor tolerogenic functions (41,42). cDC may also favor Th17 differentiation during the elimination of infected apoptotic cells (33). This requires both TLR triggering and TGF-b synthesis because of apoptotic cell uptake (33).…”

Section: Discussionmentioning

confidence: 99%

TGF-β–Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

Bonnefoy

Couturier

Clauzon

et al. 2011

The Journal of Immunology

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“…In the case of DA virus infection, apoptotic activity induced by this slowergrowing virus may limit replication; in addition, the block in type I IFN production may foster virus persistence. Later during the infection, L-induced apoptosis of DA virus-infected cells may set the stage for the immune-mediated demyelinating disease, since innate recognition of infected apoptotic cells induces a T-helper-17 adaptive immune response that is associated with autoimmune diseases (25). In persistently infected oligodendrocytes, the continuing production of low levels of type I IFN may modulate the expression of L, leading to dysfunction of oligodendrocytes, thereby contributing to the subsequent demyelination (23).…”

Section: Discussionmentioning

confidence: 99%

Apoptotic and Antiapoptotic Activity of L Protein of Theiler's Murine Encephalomyelitis Virus

Stavrou¹,

Ghadge²

2011

J Virol

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Viruses frequently have genes with proapoptotic or antiapoptotic activity that may vary in different cell types. The apoptosis that is induced can trigger either a protective or destructive immune response, thereby facilitating virus clearance or persistence of the virus. Apoptotic and antiapoptotic genes have been identified in a number of picornaviruses (reviewed in reference 1). Genes regulating apoptosis in Theiler's murine encephalomyelitis virus (TMEV) have been of special interest because of their potential importance in the pathogenesis of TMEV-induced diseases (reviewed in reference 16).TMEV is a member of the Theilovirus species of the Cardiovirus genus of the Picornaviridae; the Cardiovirus genus also includes the Encephalomyocarditis virus (EMCV) species, which comprises EMCV and mengovirus. TMEV strains can be divided into two subgroups on the basis of their differing biological properties. The GDVII strain and other members of the GDVII subgroup of TMEV are highly virulent and produce a fatal, acute polioencephalomyelitis in mice with no persistence of the virus. In contrast, DA, BeAn, and other members of the less-virulent TO subgroup induce an early transient subclinical neuronal disease followed by a chronic progressive inflammatory demyelination, TMEV-induced demyelinating disease (TMEV-IDD), with persistence of the virus in the central nervous system (CNS) for the life of the mouse. During TMEV-IDD, relatively large amounts of the TMEV genome persist in oligodendrocytes and microglia, with low levels of infectious virus and viral antigen, i.e., there is a restricted expression of DA viral proteins. TMEV-IDD serves as a model of multiple sclerosis because of the similarity in the demyelinating pathology and because the immune system appears to contribute to pathology in both disorders. The remarkable disease phenotype of TO subgroup strains has made TMEV a subject of continuing interest.Apoptosis has been described during early infection of mice with strains from both subgroups of TMEV and during the late TMEV-IDD. During TMEV-IDD, apoptosis of T cells, microglia/macrophages, and oligodendrocytes has been described (2,5,20,26). In vitro studies have implicated the cardiovirus L protein, which is encoded between the start of the polyprotein and the P1 capsid proteins (Fig. 1), in regulating apoptosis. In vitro studies of TMEV carried out by Fan et al. (9) showed that transfection of an expression construct of BeAn L into BHK-21 cells and a mouse macrophage cell line led to cell death and apoptosis, while Romanova et al. (18) found that L of other cardioviruses has antiapoptotic activity, since infection with a mengovirus with a mutation in the L zinc-binding domain led to apoptosis of HeLa cells that was not seen following wild-type (wt) mengovirus infection. In order to clarify the latter observations and further characterize the apoptotic activity of TMEV, we investigated apoptosis in different cell types following transfection of DA and GDVII L expression constructs and following infection ...

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“…ducts that activate Toll-like receptors (24). In addition to apoptosis, Th17 development also is associated with IL-10 induction (24); we observed high IL-10 levels in the wild-type infection (Fig.…”

Section: Resultsmentioning

confidence: 74%

“…These findings suggest a role for bacterial chemotaxis in eliciting a Th17 response. Th17 responses have been implicated in Citrobacter rodentium (23) and Salmonella enterica serovar Typhimurium infections (24), where these responses seem to underlie pathology.…”

Section: Resultsmentioning

confidence: 99%

Bacterial chemotaxis modulates host cell apoptosis to establish a T-helper cell, type 17 (Th17)-dominant immune response in Helicobacter pylori infection

Rolig¹,

Carter

Ottemann

2011

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

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The host inflammatory response to chronic bacterial infections often dictates the disease outcome. In the case of the gastric pathogen Helicobacter pylori, host inflammatory responses result in outcomes that range from moderate and asymptomatic to more severe with concomitant ulcer or cancers. It was found recently that H. pylori chemotaxis mutants (Che − ), which lack directed motility but colonize to nearly wild-type levels, trigger less host inflammation. We used these mutants to observe host immune responses that resulted in reduced disease states. Here we report that these mutants are defective for early gastric recruitment of CD4 + T cells compared with wild-type infection. Furthermore, Che − mutant infections lack the Thelper cell, type 17 (Th17) component of the immune response, as measured by cytokine mRNA levels in gastric tissue via intracellular cytokine staining and immunofluorescence. We additionally find that a Che − mutant infection results in significantly less host cell apoptosis than does wild-type infection, in accordance with previous observations that T-helper cell, type 17 responses in Citrobacter rodentium infections are driven by concomitant bacterial and apoptotic cell signals. We propose that bacterial chemotaxis allows H. pylori to access a particular host niche that allows the bacteria to express or deliver proapoptotic host cell factors. This report indicates that chemotaxis plays a role in enhancing apoptosis, suggesting bacterial chemotaxis systems might serve as therapeutic targets for infections whose symptoms arise from host cell apoptosis and tissue damage.T regulatory cells | adaptive immunity | pathogenesis

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Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation

Cited by 312 publications

References 31 publications

TGF-β–Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

TGF-β–Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

Apoptotic and Antiapoptotic Activity of L Protein of Theiler's Murine Encephalomyelitis Virus

Bacterial chemotaxis modulates host cell apoptosis to establish a T-helper cell, type 17 (Th17)-dominant immune response in Helicobacter pylori infection

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