Cutting Edge: The Acquisition of TLR Tolerance during Malaria Infection Impacts T Cell Activation

Perry, James A.; Olver, Christine S.; Burnett, Robert; Avery, Anne C.

doi:10.4049/jimmunol.174.10.5921

Cited by 108 publications

(111 citation statements)

References 30 publications

(28 reference statements)

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“…Moreover, although T-cell hyporesponsiveness was observed during infection, it occurred to the same extent in PyL and PyNL infections and seemed to result from failure of CD11b ϩ APCs from infected animals to drive IL-2-dependent T-cell proliferation. These results are in agreement with previous studies with P. yoelii (26,37) in which it was suggested that T-cell hyporesponsiveness during malaria infection was due to the acquisition of Toll-like receptor tolerance (26,37) and mediated, by a soluble mediator that is not nitric oxide, prostaglandin E2, or TGF-␤ (26). We have confirmed that this downmodulation of T-cell activation is not mediated by TGF-␤ alone (data not shown), but we cannot yet rule out the possibility that TGF-␤ might act in combination with other regulatory molecules.…”

Section: Discussionsupporting

confidence: 83%

“…IL-10 production by APCs themselves appears to be minimal in this situation. These data thus both confirm and significantly extend observations from the P. yoelii, P. chabaudi, and P. berghei infection models in which the primary defect appears to be at the level of the APC (26,29,37,53). Clearly, by 7 days p.i., splenic CD4 ϩ T cells from P. yoelii-infected mice have lost their ability to make and respond to IL-2 by proliferation, but they have enhanced capacity for production of both IFN-␥ and IL-10, and both of these cytokines are more abundantly produced by T cells from PyL-infected mice than by T cells from PyNLinfected mice.…”

Section: P Yoelii-induced T-cell Hyporesponsiveness Is Both Cd11bsupporting

confidence: 78%

“…Antigen-presenting cells (APCs) produce interleukin 12 (IL-12), IL-15, IL-18, and tumor necrosis factor alpha (TNF-␣) (17,26,31,32,37,38,40,44,45,48), which can rapidly activate cells of the innate immune system to produce gamma interferon (IFN-␥) (31,32,44,64). After several days (around 5 days in mice), IFN-␥ from ␣␤ T cells begins to dominate the response.…”

mentioning

confidence: 99%

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Macrophage-Mediated but Gamma Interferon-Independent Innate Immune Responses Control the Primary Wave ofPlasmodium yoeliiParasitemia

et al. 2007

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In most models of blood-stage malaria infection, proinflammatory immune responses are required for control of infection and elimination of parasites. We hypothesized therefore that the fulminant infections caused in mice by the lethal strain of Plasmodium yoelii (17XL) might be due to failure to activate a sufficient inflammatory response. Here we have compared the adaptive CD4 ؉ T-cell and innate immune response to P. yoelii 17XL with that induced by the self-resolving, nonlethal strain of P. yoelii, 17X(NL). During the first 7 to 9 days of infection, splenic effector CD4 ؉ T-cell responses were similar in mice with lethal and nonlethal infections with similar levels of activation in vivo and equivalent proliferation in vitro following mitogenic stimulation. Nonspecific T-cell hyporesponsiveness was observed at similar levels during both infections and was due, in part, to suppression mediated by CD11b ؉ cells. Importantly, however, RAG ؊/؊ mice were able to control the initial growth phase of nonlethal P. yoelii infection as effectively as wild-type mice, indicating that T cells and/or B cells play little, if any, role in control of the primary peak of parasitemia. Somewhat unexpectedly, we could find no clear role for either NK cells or gamma interferon (IFN-␥) in controlling primary P. yoelii infection. In contrast, depletion of monocytes/macrophages exacerbated parasite growth and anemia during both lethal and nonlethal acute P. yoelii infections, indicating that there is an IFN-␥-, NK cell-, and T-cell-independent pathway for induction of effector macrophages during acute malaria infection.

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Section: Discussionsupporting

confidence: 83%

Section: P Yoelii-induced T-cell Hyporesponsiveness Is Both Cd11bsupporting

confidence: 78%

mentioning

confidence: 99%

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Macrophage-Mediated but Gamma Interferon-Independent Innate Immune Responses Control the Primary Wave ofPlasmodium yoeliiParasitemia

et al. 2007

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“…Among a variety of immune evasion mechanisms, DCs, which play central roles in establishing immunity, are the major target for malaria parasites. For instance, malaria parasites interfere with the maturation of DCs (3,36,37) or prevent Ag cross-presentation (38), both of which result in the failure to directly activate protective/effector T cells. Unlike these observations, our findings propose a novel interaction of malaria parasites with DCs via TLR9 that affects Tregs rather than protective T cells.…”

Section: Discussionmentioning

confidence: 99%

Malaria Parasites Require TLR9 Signaling for Immune Evasion by Activating Regulatory T Cells

Hisaeda

Tetsutani

Imai

et al. 2008

The Journal of Immunology

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Malaria is still a life-threatening infectious disease that continues to produce 2 million deaths annually. Malaria parasites have acquired immune escape mechanisms and prevent the development of sterile immunity. Regulatory T cells (Tregs) have been reported to contribute to immune evasion during malaria in mice and humans, suggesting that activating Tregs is one of the mechanisms by which malaria parasites subvert host immune systems. However, little is known about how these parasites activate Tregs. We herein show that TLR9 signaling to dendritic cells (DCs) is crucial for activation of Tregs. Infection of mice with the rodent malaria parasite Plasmodium yoelii activates Tregs, leading to enhancement of their suppressive function. In vitro activation of Tregs requires the interaction of DCs with parasites in a TLR9-dependent manner. Furthermore, TLR9−/− mice are partially resistant to lethal infection, and this is associated with impaired activation of Tregs and subsequent development of effector T cells. Thus, malaria parasites require TLR9 to activate Tregs for immune escape.

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“…However, the relevance of repeated high-dose stimulation of TLR7 to human disease is unclear. Repeated administration of TLR9 agonist disrupts lymph node and splenic architecture [42] and repeated dosing in a rapid schedule induces TLR signalling tolerance [43]. Either mechanism may explain disease inhibition following repeated exposure to high doses of TLR7/8 or TLR9 agonists.…”

Section: Tlr7/9 Agonists Activate Nod-derived Bmdcs and Cause The Secmentioning

confidence: 99%

Toll-like receptor 7 stimulation promotes autoimmune diabetes in the NOD mouse

et al. 2011

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Aims/hypothesis The role of Toll-like receptor 7 (TLR7), a sensor of viral and self RNA, in promoting autoimmune diabetes remains unclear. Our goal was to determine the effect of TLR7 stimulation on the priming and activation of diabetogenic CD8 + T cells. Methods We explored the effects of CL097 (TLR7/8 agonist) and immunoregulatory sequence 661 (IRS661, TLR7 inhibitor) on bone marrow-derived dendritic cells (BMDCs), diabetogenic CD8 + T cell function and autoimmune diabetes onset in NOD and 8.3 NOD T cell receptor transgenic mice (8.3 NOD mice). Results TLR7 stimulation of NOD BMDCs increased activation and production of proinflammatory cytokines. In vivo administration of CL097 activated T cells and dendritic cells and increased levels of proinflammatory cytokines and type 1/2 IFNs in NOD mice. In vivo antigen-specific cytotoxicity studies revealed enhanced cytotoxicity against islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP, an islet autoantigen) peptide pulsed targets in NOD mice treated with CL097 plus CD40 agonist. This combination treatment accelerated the onset of autoimmune diabetes in 8.3 NOD mice. Likewise, topical treatment of NOD mice with a TLR7 agonist accelerated diabetes onset. Spontaneous disease in 8.3 NOD mice and accelerated disease in CL097+CD40 agonist-treated 8.3 NOD mice were delayed by IRS661 treatment, which is associated with inhibition of the endogenous upregulation of IFN-α levels within the pancreatic lymph nodes. Conclusions/interpretation TLR7 stimulation accelerates the spontaneous onset of autoimmune diabetes in 8.3 NOD and NOD mice. Conversely, TLR7 inhibition prevents the early events associated with diabetogenesis.

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Cutting Edge: The Acquisition of TLR Tolerance during Malaria Infection Impacts T Cell Activation

Cited by 108 publications

References 30 publications

Macrophage-Mediated but Gamma Interferon-Independent Innate Immune Responses Control the Primary Wave ofPlasmodium yoeliiParasitemia

Macrophage-Mediated but Gamma Interferon-Independent Innate Immune Responses Control the Primary Wave ofPlasmodium yoeliiParasitemia

Malaria Parasites Require TLR9 Signaling for Immune Evasion by Activating Regulatory T Cells

Toll-like receptor 7 stimulation promotes autoimmune diabetes in the NOD mouse

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