Ligation of B and T Lymphocyte Attenuator Prevents the Genesis of Experimental Cerebral Malaria

Lepenies, Bernd; Pfeffer, Klaus; Hurchla, Michelle A.; Murphy, Theresa L.; Murphy, Kenneth M.; Oetzel, Juliane; Fleischer, Bernhard; Jacobs, Thomas

doi:10.4049/jimmunol.179.6.4093

Cited by 45 publications

(65 citation statements)

References 34 publications

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“…Both of these were shown to modulate T cell function during PbA infection. In PbA-infected C57BL/6 mice, we found that blockade of CTLA-4 leads to exacerbation of the immune pathology triggered by T cells producing proinflammatory cytokines, whereas an agonistic Ab against BTLA prevented the genesis of CM (13). This supports the idea that the induction of negative costimulators during PbA infection is a means of dampening the strong and polarized activation of the Th1 arm of the immune system to prevent immune pathology.…”

supporting

confidence: 74%

“…Several studies have shown that during experimental malaria infection different regulatory mechanisms are triggered to avoid overwhelming pathology, such as production of IL-10 and TGF-ß (35,36). We have found that the negative costimulators CTLA-4 and BTLA expressed on T cells play a critical role during PbA infection by dampening the immune response (11)(12)(13). Recently, it was found that CTLA-4 is not only expressed by Foxp3 ϩ T reg constitutively, but is also critical for their function (37).…”

Section: Discussionmentioning

confidence: 82%

“…Various studies clearly demonstrated a role for T cells secreting proinflammatory cytokines for the genesis of CM (7)(8)(9)(10). We recently found that T cell activation during malaria is accompanied by an increased expression of the negative costimulators CTLA-4 (11,12) and B and T lymphocyte attenuator (BTLA) (13). Both of these were shown to modulate T cell function during PbA infection.…”

mentioning

confidence: 96%

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Limited Role of CD4+Foxp3+ Regulatory T Cells in the Control of Experimental Cerebral Malaria

Steeg

Adler

Sparwasser

et al. 2009

The Journal of Immunology

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Cerebral malaria (CM) associated with Plasmodium berghei ANKA (PbA) infection is an accepted model of human CM. CM during PbA infection critically depends on sequestration of T cells into the brain. Several studies aimed to address the role of regulatory T cells (Treg) in modulating this pathogenic T cell response. However, these studies are principally hampered due to the fact that until recently no reagents were available to deplete Foxp3+ Treg specifically. To study the function of Treg in the genesis of CM, we used depletion of Treg mice that are transgenic for a bacterial artificial chromosome expressing a diphtheria toxin receptor-enhanced GFP fusion protein under the control of the foxp3 gene locus. These mice allow for a selective depletion of Foxp3+ Treg by diphtheria toxin injection, and also their specific detection and purification during an ongoing infection. Using depletion of Treg mice, we found only a small increase in the absolute numbers of Foxp3+ Treg during PbA infection and, consequently, the ratio of Treg to T effector cells (Teff) decreased due to the rapid expansion of Teff. Although the latter sequester in the brains of infected mice, almost no Treg were found in the brains of infected mice. Furthermore, we demonstrate that depletion of Treg has no influence on sequestration of Teff and on the clinical outcome, and only minor influence on T cell activation. Using ex vivo analysis of purified Treg from either naive mice or PbA-infected mice, we found that both exhibit similar inhibitory capacity on Teff.

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confidence: 74%

Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 96%

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Limited Role of CD4+Foxp3+ Regulatory T Cells in the Control of Experimental Cerebral Malaria

Steeg

Adler

Sparwasser

et al. 2009

The Journal of Immunology

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“…BTLA expression was also found to be highly induced on anergic CD4+ T cells [59]. The treatment of mice infected with Plasmodium berghei ANKA with an agonist anti-BTLA mAb prevented the genesis of experimental cerebral malaria by restricting the number of T lymphocytes sequestered in the brain during infection [60]. Until recently, the hyperproliferative response of BTLA-deficient T cells to immobilized anti-CD3 was thought to reflect the loss of a negative costimulatory signals on T cells [61].…”

Section: Functions In Host Defense Regulated By Tnfr Superfamilymentioning

confidence: 99%

The TNF receptor and Ig superfamily members form an integrated signaling circuit controlling dendritic cell homeostasis

Trez

Ware

2008

Cytokine & Growth Factor Reviews

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Dendritic cells (DC) constitute the most potent antigen presenting cells of the immune system, playing a key role bridging innate and adaptive immune responses. Specialized DC subsets differ depending on their origin, tissue location and the influence of trophic factors, the latter remain to be fully understood. Stromal cell and myeloid-associated Lymphotoxin-β receptor (LTβR) signaling is required for the local proliferation of lymphoid tissue DC. This review focuses the LTβR signaling cascade as a crucial positive trophic signal in the homeostasis of DC subsets. The noncanonical coreceptor pathway comprised of the Immunoglobulin (Ig) superfamily member, B and T lymphocyte attenuator (BTLA) and TNFR superfamily member, Herpesvirus entry mediator (HVEM) counter regulates the trophic signaling by LTβR. Together both pathways form an integrated signaling circuit achieving homeostasis of DC subsets.Keywords dendritic cells; homeostasis; TNF superfamily; cosignaling; lymphotoxin; herpesvirus entry mediator Dendritic CellsDendritic cells (DC) originate from hematopoietic precursors and can be divided in several subsets depending on their anatomical location, surface phenotype and function. For example, two broad classes of DC are the peripheral migratory DC and the lymphoid tissue-resident DC [1]. The migratory DC, i.e. the dermal DC and Langerhans cells, can be considered as sentinels of the immune system as they form a sensing barrier in peripheral tissues at the interface with environment. The lymphoid tissue-resident DC include the splenic and thymic DC.Dendritic cells are specialized in the capture, transport, processing and presentation of antigens. In the presence of a microbial stimulus, these steps are associated with further DC differentiation (maturation) characterized by upregulation of costimulatory and major histocompatibility complex (MHC) molecules. As DC become activated they migrate to or Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Both spleen and lymph node lymphoid tissue-resident DC possess a half-life of about three days. Despite their rapid turnover, little is known about the factors controlling immediate precursors and homeostasis in vivo. In earlier studies, CD8α expression was used to distinguish between "lymphoid" and "myeloid" DC. However, more recent experiments showed that different DC subsets could differentiate from both lymphoid and myeloid precursors [6,7]. CD8α marker remains very useful to discriminate between subsets, but no longer defines a subset origin. Recently, the group of Shortman provided in vivo and in vitro evidence fo...

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“…injection of 1 3 10 6 PbA-infected erythrocytes as described previously (37). Parasitemia was determined by examining Wright-stained tail blood smears on glass slides, and results were expressed as the percentage of infected RBCs.…”

Section: Ethics Statementmentioning

confidence: 99%

The C-Type Lectin Receptor DCIR Is Crucial for the Development of Experimental Cerebral Malaria

Maglinao

Klopfleisch

Seeberger

et al. 2013

The Journal of Immunology

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Cerebral malaria (CM) is the most severe complication of malaria. The murine Plasmodium berghei ANKA (PbA) infection model has helped to identify crucial players in the pathogenesis of CM. However, the role of pattern recognition receptors in innate immunity to CM induction is still poorly understood. C-type lectin receptors (CLRs) represent a family of pattern recognition receptors that recognize carbohydrate structures on pathogens and self-Ags often in a Ca2+-dependent manner. In this study, we investigated the role of the CLR dendritic cell immunoreceptor (DCIR) in the genesis of CM. Using the murine PbA infection, we show in this article that DCIR is essential for the development of CM. Although PbA infection led to 80% CM in wild-type C57BL/6 mice, DCIR-deficient mice were highly protected with only 15% CM development. In accordance with the reduced CM incidence in DCIR−/− mice, CD8+ T cell sequestration was markedly reduced in brains of PbA-infected DCIR−/− mice, which was accompanied by reduced brain inflammation. Reduced T cell sequestration in the brain was caused by decreased TNF-α levels in sera, as well as a modulated activation of CD4+ and CD8+ T cells in spleen of PbA-infected DCIR−/− mice. This study indicates that DCIR is critically involved in CM induction, thus highlighting the importance of this CLR in innate immunity during malaria infection.

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Ligation of B and T Lymphocyte Attenuator Prevents the Genesis of Experimental Cerebral Malaria

Cited by 45 publications

References 34 publications

Limited Role of CD4+Foxp3+ Regulatory T Cells in the Control of Experimental Cerebral Malaria

Limited Role of CD4+Foxp3+ Regulatory T Cells in the Control of Experimental Cerebral Malaria

The TNF receptor and Ig superfamily members form an integrated signaling circuit controlling dendritic cell homeostasis

The C-Type Lectin Receptor DCIR Is Crucial for the Development of Experimental Cerebral Malaria

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