Cooperation of TLR12 and TLR11 in the IRF8-Dependent IL-12 Response to <i>Toxoplasma gondii</i> Profilin

Raetz, Megan; Kibardin, Alexey; Sturge, Carolyn R.; Pifer, Reed; Li, Haiying; Burstein, Ezra; Ozato, Keiko; Larin, Sergey; Yarovinsky, Felix

doi:10.4049/jimmunol.1301301

Cited by 103 publications

(98 citation statements)

References 50 publications

(69 reference statements)

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“…T. gondii-infected mice blocked for IFN-␥ or depleted of NK cells demonstrate impaired maturation of DCs and inflammatory monocytes, increased numbers of resident macrophages, and decreased IL-12 production by DCs (49). The ability of monocytes to respond to IFN-␥ priming is necessary for increased activation of monocytes and for IL-12 production by monocyte-derived DCs in response to T. gondii infection (49,50). On the molecular level, it has been shown that IFN-␥ enhances the production and transcription of IL-12 via induction of regulatory transcription factor 8 (IRF8), a major transcriptional factor regulating IL-12p40 and IL-12p35 transcription (50,51).…”

Section: Ifn-␥-producing Cells: From T To Nk Cells and Neutrophilsmentioning

confidence: 99%

“…The ability of monocytes to respond to IFN-␥ priming is necessary for increased activation of monocytes and for IL-12 production by monocyte-derived DCs in response to T. gondii infection (49,50). On the molecular level, it has been shown that IFN-␥ enhances the production and transcription of IL-12 via induction of regulatory transcription factor 8 (IRF8), a major transcriptional factor regulating IL-12p40 and IL-12p35 transcription (50,51). Together, these results indicate that NK cells are a critical effector component of the innate immune response-able to effectively prime monocytes and DCs for parasite recognition while mediating T cell-independent IFN-␥-dependent host protection from the parasite.…”

Section: Ifn-␥-producing Cells: From T To Nk Cells and Neutrophilsmentioning

confidence: 99%

“…Pattern recognition receptors, such as TLRs, are innate immune receptors involved in recognizing conserved molecules present on bacteria, viruses, and parasites which are not expressed by the host cells. In mice, recognition of T. gondii profilin is mediated by TLR11, which directly binds profilin, forms a heterodimer with TLR12, and recruits the TLR adaptor protein MyD88 (4,5,50). Recent data suggest that TLR12 can function independently of TLR11 in plasmacytoid DCs (pDCs).…”

Section: Il-12 Production Is Essential For Ifn-␥ Production By Nk mentioning

confidence: 99%

“…This discrepancy regarding the TLR dependence of pDC IL-12 needs to be clarified, as does the observed dependence of IFN-␣ on TLR12. Furthermore, how TLR12 can trigger cytokine production in the absence of TLR11 is a mystery because, in contrast to TLR11, TLR12 fails to biochemically interact with MyD88 (50).…”

Section: Il-12 Production Is Essential For Ifn-␥ Production By Nk mentioning

confidence: 99%

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Complex Immune Cell Interplay in the Gamma Interferon Response during Toxoplasma gondii Infection

2014

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Toxoplasma gondii is an obligate intracellular parasite of clinical importance, especially in immunocompromised patients. Investigations into the immune response to the parasite found that T cells are the primary effector cells regulating gamma interferon (IFN-␥)-mediated host resistance. However, recent studies have revealed a critical role for the innate immune system in mediating host defense independently of the T cell responses to the parasite. This body of knowledge is put into perspective by the unifying theme that immunity to the protozoan parasite requires a strong IFN-␥ host response. In the following review, we discuss the role of IFN-␥-producing cells and the signals that regulate IFN-␥ production during T. gondii infection.

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Section: Ifn-␥-producing Cells: From T To Nk Cells and Neutrophilsmentioning

confidence: 99%

Section: Ifn-␥-producing Cells: From T To Nk Cells and Neutrophilsmentioning

confidence: 99%

Section: Il-12 Production Is Essential For Ifn-␥ Production By Nk mentioning

confidence: 99%

Section: Il-12 Production Is Essential For Ifn-␥ Production By Nk mentioning

confidence: 99%

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Complex Immune Cell Interplay in the Gamma Interferon Response during Toxoplasma gondii Infection

2014

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“…The persistence of infection requires not only the acute induction of immune mechanisms that control parasite hyperproliferation but also efficient dissemination of parasites into deep tissues, where they establish a chronic niche. A concept that is now gaining acceptance is that induction of proinflammatory cytokines essential for in vivo control of acute Toxoplasma infection involves intracellular signaling from endosomal and cytoplasmic pattern recognition receptors (PRRs) (22)(23)(24)(25)(26). Interestingly, the inflammatory cytokines IL-12 and IL-1β are both induced differentially by avirulent, but not virulent, Toxoplasma strains (9,27,28), presumably through intracellular activation of TLRs and other PRRs.…”

Section: Discussionmentioning

confidence: 99%

Avirulent strains of Toxoplasma gondii infect macrophages by active invasion from the phagosome

Zhao

Marple

Ferguson

et al. 2014

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

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Unlike most intracellular pathogens that gain access into host cells through endocytic pathways, Toxoplasma gondii initiates infection at the cell surface by active penetration through a moving junction and subsequent formation of a parasitophorous vacuole. Here, we describe a noncanonical pathway for T. gondii infection of macrophages, in which parasites are initially internalized through phagocytosis, and then actively invade from within a phagosomal compartment to form a parasitophorous vacuole. This phagosome to vacuole invasion (PTVI) pathway may represent an intermediary link between the endocytic and the penetrative routes for host cell entry by intracellular pathogens. The PTVI pathway is preferentially used by avirulent strains of T. gondii and confers an infectious advantage over virulent strains for macrophage tropism.virulence | Trojan horse | apicomplexa | phagocytes P hagocytosis is one of the most ancient defense mechanisms for the host to destroy invasive pathogens. However, most intracellular pathogens exploit this very pathway for internalization and survival in phagocytes (1). A notable exception to this paradigm is the infection pathway used by apicomplexan parasites-exemplified by Toxoplasma gondii. The current consensus model of T. gondii infection suggests that the parasite actively invades host cells by forming a moving junction (MJ) at the host cell surface (2). Penetration of T. gondii through this junction is largely driven by its own actin motor complex (3). The parasitophorous vacuoles formed by this pathway are nonfusogenic with the host endocytic system, thus evading lysosome-mediated destruction (4-6). However, recent reports including the findings that host F-actin participates in entry by T. gondii (7), and that the parasite is still able to infect cells, albeit much less efficiently, even without some key components of the invasion machinery (8), suggest the existence of alternative infection pathways for Toxoplasma. The active penetration model was defined largely by using nonphagocytic host cells and hypervirulent strains of the parasite. Unlike their virulent counterparts, the interaction of avirulent Toxoplasma strains with macrophage and dendritic cell results in heightened innate cytokine and chemokine production (9) and the development of a "hypermotile" host cellular phenotype (10), which promotes the control of acute infection and mediates dissemination into sites of parasite latency (11,12). Here, we investigated whether avirulent parasites interact with phagocytic host cells in a fundamentally different way from the outset. We found that the avirulent Toxoplasma strains infect macrophages initially via phagocytosis and subsequent active penetration from within the phagosome to form a parasitophorous vacuole. This hybrid invasion pathway may represent an intermediary link between the endocytic and the penetrative routes for host cell entry by intracellular pathogens. ResultsTo investigate whether avirulent Toxoplasma (PTG, type II strain) uses the active penetration p...

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Dendritic cell maturation: functional specialization through signaling specificity and transcriptional programming

et al. 2014

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Dendritic cells (DC) are key regulators of both protective immune responses and tolerance to self-antigens. Soon after their discovery in lymphoid tissues by Steinman and Cohn, as cells with the unique ability to prime naïve antigen-specific T cells, it was realized that DC can exist in at least two distinctive states characterized by morphological, phenotypic and functional changes-this led to the description of DC maturation. It is now well appreciated that there are several subsets of DC in both lymphoid and non-lymphoid tissues of mammals, and these cells show remarkable functional specialization and specificity in their roles in tolerance and immunity. This review will focus on the specific characteristics of DC subsets and how their functional specialization may be regulated by distinctive gene expression programs and signaling responses in both steady-state and in the context of inflammation. In particular, we will highlight the common and distinctive genes and signaling pathways that are associated with the functional maturation of DC subsets. Dendritic cell heterogeneityDendritic cells are cells of the mononuclear phagocyte system and develop in the bone marrow from common DC precursors that give rise to plasmacytoid DCs (pDCs) and to intermediate cells known as pre-conventional DC (pre-cDC). After exiting the bone marrow, precDC transiently circulate in the bloodstream and migrate into lymphoid and non-lymphoid tissues where they differentiate into cDC, pDC also enter tissues from the blood stream, constitutively in the case of secondary lymphoid organs but only upon inflammation in the case of non-lymphoid tissues. Analysis of secondary lymphoid organs (spleen, lymph nodes) and of non-lymphoid tissues (skin, intestine, lung, skeletal muscle and liver) has led to the identification of several distinct populations of cDC. Regardless of their anatomical location or species of origin, cDC can be grouped into two major subsets based on their phenotype, gene expression program, functional specialization and the transcription factors that specify their development (Guilliams et al, 2010) (Fig 1).Xcr1 + and CD11b + cDC The expression of CD8a or CD103 at the cell surface was originally used to classify a subset of cDC, often referred to as CD8a-type cDC. However, CD8a expression does not constitute a "universal" marker of this subset and CD103 is also expressed by intestinal cDC belonging to a second subset known as CD11b + cDC (see below). In contrast, the chemokine receptor Xcr1 has been recently shown to be strictly specific for CD8a-type cDC (Bachem et al, 2012;Crozat et al, 2011). The C-type lectin Clec9a (also known as Dngr1) is also selectively expressed on CD8a-type cDC, but also on pDC and on a subset of DC progenitors (Schraml et al, 2013). On that basis, CD8a-type cDC will be denoted as Xcr1 + cDC for the purpose of this review. The human DC subset often referred to as CD141 (BDCA3) + cDC, is the equivalent of mouse Xcr1 + cDC (Robbins et al, 2008; Haniffa et al, 2012) and can also be ide...

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Cooperation of TLR12 and TLR11 in the IRF8-Dependent IL-12 Response to Toxoplasma gondii Profilin

Cited by 103 publications

References 50 publications

Complex Immune Cell Interplay in the Gamma Interferon Response during Toxoplasma gondii Infection

Complex Immune Cell Interplay in the Gamma Interferon Response during Toxoplasma gondii Infection

Avirulent strains of Toxoplasma gondii infect macrophages by active invasion from the phagosome

Dendritic cell maturation: functional specialization through signaling specificity and transcriptional programming

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