IL-12 Is Required for Antibody-Mediated Protective Immunity Against Blood-Stage<i>Plasmodium</i> <i>chabaudi</i>AS Malaria Infection in Mice

Su, Zhendong; Stevenson, Mary M.

doi:10.4049/jimmunol.168.3.1348

Cited by 166 publications

(160 citation statements)

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“…Thus, CD8 + DC may not only be crucial for initiation of CD8 + T cell responses leading to ECM, but also for promoting Th1 cell development that in turn facilitates IFN-g-dependent CD8 + T cell recruitment to this organ. Alternatively, control of P. chabaudi infection largely requires Th1 cells during the first peak of parasitemia (84) and Tfh cells for complete elimination of the parasite (85). Tfh cells secrete several cytokines, such as IFN-g, IL-2, IL-4, and IL-21.…”

Section: Discussionmentioning

confidence: 99%

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

Fernandez‐Ruiz

Lau

Ghazanfari

et al. 2017

The Journal of Immunology

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We describe an MHC class II (I-Ab)–restricted TCR transgenic mouse line that produces CD4+ T cells specific for Plasmodium species. This line, termed PbT-II, was derived from a CD4+ T cell hybridoma generated to blood-stage Plasmodium berghei ANKA (PbA). PbT-II cells responded to all Plasmodium species and stages tested so far, including rodent (PbA, P. berghei NK65, Plasmodium chabaudi AS, and Plasmodium yoelii 17XNL) and human (Plasmodium falciparum) blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of Ab to P. chabaudi infection and can control this otherwise lethal infection in CD40L-deficient mice. PbT-II cells can also provide help for development of CD8+ T cell–mediated experimental cerebral malaria (ECM) during PbA infection. Using PbT-II CD4+ T cells and the previously described PbT-I CD8+ T cells, we determined the dendritic cell (DC) subsets responsible for immunity to PbA blood-stage infection. CD8+ DC (a subset of XCR1+ DC) were the major APC responsible for activation of both T cell subsets, although other DC also contributed to CD4+ T cell responses. Depletion of CD8+ DC at the beginning of infection prevented ECM development and impaired both Th1 and follicular Th cell responses; in contrast, late depletion did not affect ECM. This study describes a novel and versatile tool for examining CD4+ T cell immunity during malaria and provides evidence that CD4+ T cell help, acting via CD40L signaling, can promote immunity or pathology to blood-stage malaria largely through Ag presentation by CD8+ DC.

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Section: Discussionmentioning

confidence: 99%

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

Fernandez‐Ruiz

Lau

Ghazanfari

et al. 2017

The Journal of Immunology

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“…It should be emphasized that the predisposing locus may not be located within the peak of linkage and that there is accumulating evidence for a role of IL12 in malaria. [13][14][15][16][17][18][19] We, therefore, searched for IL12B polymorphisms in the whole coding sequence, including the intron-exon borders, and genotyped cis-regulatory polymorphisms within the promoter and the 3 0 UTR region in individuals living in an endemic area. We did not find any polymorphism within the coding sequence, indicating a high level of conservation of IL12B in African populations, as previously suggested in Caucasian populations.…”

Section: Il12b In Human Malariamentioning

confidence: 99%

“…13,14 Studies with IL-12p40-deficient mice confirmed the effect of IL-12 in the protection against P. chabaudi. 15,16 In humans, low levels of IL-12 have been associated with severe malaria 17,18 and increased parasitemia. 19 In addition, a promoter polymorphism in IL12B (rs17860508), which is thought to influence the production of IL-12, 20,21 was associated with increased mortality from cerebral malaria in Tanzanian children.…”

Section: Introductionmentioning

confidence: 99%

IL12B polymorphisms are linked but not associated with Plasmodium falciparum parasitemia: a familial study in Burkina Faso

et al. 2008

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Chromosome 5q31-q33 has been linked to Plasmodium falciparum parasitemia in several independent studies. This chromosomal region contains numerous immunoregulatory genes. Among these, IL12B that encodes the p40 subunit of interleukin-12 (IL-12) appeared to be a promising functional candidate gene, and IL12Bpro, a promoter polymorphism, was associated with mortality from severe malaria in children. In this study, we characterized genetic variation in IL12B in 215 individuals belonging to 34 families and evaluated linkage and association of parasitemia with IL12B polymorphisms and haplotypes. We searched for IL12B polymorphisms in the coding regions and the corresponding intron-exon borders. We also examined IL12Bpro and IL12B 3 0 untranslated region (UTR) polymorphisms, which are thought to influence the production of IL-12. We showed a high level of conservation of IL12B-coding regions and identified five polymorphisms in introns and the two polymorphisms in the promoter and the 3 0 UTR regions. Although IL12B polymorphisms were linked to parasitemia, there was association of parasitemia with neither polymorphisms nor haplotypes. We cannot exclude that an unknown IL12B cis-regulatory element polymorphism affects both IL-12 production and parasitemia. However, our results suggest that genetic variation in IL12B does not explain differences in parasitemia in individuals living in an endemic area.

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“…Bloodstage malaria infections were initiated by i.p. injection of 1 × 10 6 pRBCs and parasitemia was monitored daily by examination of Giemsa-stained (Sigma-Aldrich, MO, USA) thin smears of tail blood [35]. The infected mice were monitored closely.…”

Section: Mice and Parasitesmentioning

confidence: 99%

Role of IL‐10‐producing regulatory B cells in control of cerebral malaria in Plasmodium berghei infected mice

Liu

Chen

et al. 2013

Eur J Immunol

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IntroductionMalaria caused by infection with protozoan parasites of Plasmodium spp. is one of the most serious infectious diseases of humans and causes about one million deaths annually. Plasmodium infection may induce multiple disease syndromes including severe anemia, metabolic acidosis, and neurological dysfunction, e.g. cerebral malaria (CM) [1]. Sequestration of the Correspondence: Dr. Zhong Su e-mail: su_zhong@gibh.ac.cn parasitized red blood cells (pRBCs) in brain microvessels is a characteristic histopathology feature observed in human and murine CM and is believed to be the primary cause of the neurological syndrome [2,3]. Evidence from more recent studies supports the notion that CM is an immune-driven pathology. The proinflammatory cytokines and mediators produced in the "cytokine storm" during malaria induce activation and recruitment of cytotoxic CD8 + cells in brain blood vessels and upregulate the expression of adhesion receptors by brain endothelial cells, leading to leukocyte accumulation and capillary obstruction, cerebral hemorrhage, and hypoxia in brain tissues [1,[4][5][6]. Therefore, the immune regulatory cells and cytokines may be critical in counteracting the inflammatory response and prevention of malaria-associated www.eji-journal.eu 2908 Yunfeng Liu et al. Eur. J. Immunol. 2013. 43: 2907-2918 neuropathology. The levels of anti-inflammatory cytokines such as IL-10 and TGF-β have been shown to be inversely associated with the occurrence of CM in murine malaria [7,8]. However, no consensus has been reached concerning the role of regulatory T (Treg) cells in regulation of CM pathogenesis [9][10][11].B cells have been traditionally considered antibody-producing cell and APC. Many studies in recent years showed the existence of a subset of B cells that exhibit the immune regulatory functions (reviewed in [12]). An early study by Fillatreau et al.[13] reported a subset of B cells that produce IL-10 and inhibit the immune pathology in murine EAE. Further studies revealed that these regulatory B (Breg) cells play important roles in control of immunopathology in autoimmune diseases [14], cancer [15], and organ transplantation [16]. Breg cells have also been shown to modulate immune responses and immunopathology in infectious diseases. Protective immunities against Salmonella typhimurium and Brucella abortus infections were inhibited by transfer of Breg cells in mouse models [17,18]. Transfer of CD1d + CD5 hi Breg cells rendered the BALB/c mice more susceptible to Leishmania major infection [19]. Adoptive transfer of IL-10-producing B cells isolated from helminth-infected mice inhibited the allergic responses and autoimmune inflammation in recipient mice [20]. Thus, Breg cells are an important component of immunoregulatory system and plays critical roles in immune homeostasis.The immunomodulatory roles of Breg cells have been studied in autoimmune and infectious disease settings, but little is known of its role in regulation of immune response and immunopathology of malaria. In this study, we i...

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IL-12 Is Required for Antibody-Mediated Protective Immunity Against Blood-StagePlasmodium chabaudiAS Malaria Infection in Mice

Cited by 166 publications

References 50 publications

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

IL12B polymorphisms are linked but not associated with Plasmodium falciparum parasitemia: a familial study in Burkina Faso

Role of IL‐10‐producing regulatory B cells in control of cerebral malaria in Plasmodium berghei infected mice

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