Escape of malaria parasites from host immunity requires CD4+CD25+ regulatory T cells

Hisaeda, Hajime; Maekawa, Yoichi; Iwakawa, Daiji; Okada, Hiroko; Himeno, Kunisuke; Kishihara, Kenji; Tsukumo, Shin-ichi; Yasutomo, Koji

doi:10.1038/nm975

Cited by 316 publications

(288 citation statements)

References 15 publications

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“…The activity of Treg during malaria has been suggested by us and others [3,16,36]. To investigate the generation of Ag-specific regulatory cells, and particularly as we detected poor memory responses, a culture experiment was set up where T cells against malaria Ag and recall Ag were simultaneously stimulated.…”

Section: Discussionmentioning

confidence: 99%

Multiple functions of human T cells generated by experimental malaria challenge

et al. 2009

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Protective immunity generated following malaria infection may be comprised of Ab or T cells against malaria Ag of different stages; however, the short-lived immunity that is observed suggests deficiency in immune memory or regulatory activity. In this study, cellular immune responses were investigated in individuals receiving Plasmodium falciparum sporozoite challenge by the natural (mosquito bite) route as part of a malaria vaccine efficacy trial. Parasitemia, monitored by blood film microscopy and PCR, was subsequently cleared with drugs. All individuals demonstrated stable IFN-c, IL-2 and IL-4 ex vivo ELISPOT effector responses against P. falciparum-infected RBC (iRBC) Ag, 28 and 90 days after challenge. However, infected RBC-specific central memory responses, as measured by IFN-c cultured ELISPOT, were low and unstable over time, despite CD4 1 T cells being highly proliferative by CFSE dilution, and showed an inverse relationship to parasite density. In support of the observation of poor memory, co-culture experiments showed reduced responses to common recall Ag, indicating malaria-specific regulatory activity. This activity could not be accounted for by the expression of IL-10, TGF-b, FOXP3 or CTLA-4, but proliferating T cells expressed high levels of CD95, indicating a pro-apoptotic phenotype. Lastly, there was an inverse relationship between FOXP3 expression, when measured 10 days after challenge, and ex vivo IFN-c measured more than 100 days later. This study shows that malaria infection elicits specific Th1 and Th2 effector cells, but concomitant weak central memory and regulatory activity, which may help to explain the short-lived immunity observed.

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Section: Discussionmentioning

confidence: 99%

Multiple functions of human T cells generated by experimental malaria challenge

et al. 2009

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“…In fact, IL-12 and CpG oligonucleotides, administered at suboptimal doses, act synergistically to restore proliferative responses in cocultures (our unpublished observations), suggesting that they could have physiological effects even at relatively low concentrations when present together in vivo. Experiments in mouse models of Leishmania and malaria indicate that, during infection, activation of antimicrobial T cells within mixed Treg/effector cell populations by IL-12 and TLR ligands could translate into more efficient and rapid clearance of pathogens (14,15). In contrast, during autoimmunity, such a phenomenon is likely to result in more severe and persistent tissue destruction.…”

Section: Discussionmentioning

confidence: 99%

Cutting Edge: IL-12 Induces CD4+CD25− T Cell Activation in the Presence of T Regulatory Cells

King¹,

Segal

2005

The Journal of Immunology

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IL-12p40 cytokines have been implicated in the development of organ-specific autoimmune diseases as well as pathogen-specific adaptive immunity. In addition to inducing IFN-γ, IL-12 stimulates effector CD4+ T cells to express adhesion molecules and homing receptors that facilitate their migration to sites of inflammation. In this study, we expand upon those observations by demonstrating an alternative pathway by which IL-12 could promote Th1 inflammatory responses in mice, namely, by restoring proliferation and cytokine expression by effector T cells in the presence of CD4+CD25+ regulatory T cells (Treg). This effect of IL-12 was not replicated by IL-23 or IFN-γ and was dependent on signaling through the IL-12R expressed on CD25− responder cells, but not on Treg. Our studies suggest that IL-12 could act in concert with other proinflammatory factors to stimulate CD4+CD25− T cell activation in the presence of Treg.

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“…Our previous findings that activation of Treg is required for immune evasion during malaria [19,20] (as assessed by the proportion of CD25 + foxp3 + cells in CD4 + cells, and by the degree of suppression of T-cell proliferation after TCR signaling (Supporting Information Fig. 1)).…”

Section: Protective Roles For Il-23 During Infection With Pbnkmentioning

confidence: 94%

IL‐23 protection against Plasmodium berghei infection in mice is partially dependent on IL‐17 from macrophages

et al. 2013

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Although IL-12 is believed to contribute to protective immune responses, the role played by IL-23 (a member of the IL-12 family) in malaria is elusive. Here, we show that IL-23 is produced during infection with Plasmodium berghei NK65. Mice deficient in IL-23 (p19KO) had higher parasitemia and died earlier than wild-type (WT) controls. Interestingly, p19KO mice had lower numbers of IL-17-producing splenic cells than their WT counterparts. Furthermore, mice deficient in IL-17 (17KO) suffered higher parasitemia than the WT controls, indicating that IL-23-mediated protection is dependent on induction of IL-17 during infection. We found that macrophages were responsible for IL-17 production in response to IL-23. We observed a striking reduction in splenic macrophages in the p19KO and 17KO mice, both of which became highly susceptible to infection. Thus, IL-17 appears to be crucial for maintenance of splenic macrophages. Adoptive transfer of macrophages into macrophage-depleted mice confirmed that macrophage-derived IL-17 is required for macrophage accumulation and parasite eradication in the recipient mice. We also found that IL-17 induces CCL2/7, which recruit macrophages. Our findings reveal a novel protective mechanism whereby IL-23, IL-17, and macrophages reduce the severity of infection with blood-stage malaria parasites. Keywords: IL-17 · IL-23 · Macrophage · Malaria · Plasmodium bergheiAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMalaria, caused by protozoan parasites of the genus Plasmodium, is still one of the most life-threatening infectious diseases. Two hundred million people are infected annually with malaria paraCorrespondence: Dr. Hajime Hisaeda e-mail: hisa@med.gunma-u.ac.jp sites while about a million people are believed to die every year from the disease [1]. Despite the urgent need for effective vaccines against malaria, progress on vaccine development has been disappointing [2]. A major obstacle for vaccine development is that the immune responses crucial for eradication of malaria * These authors contributed equally to this work. parasites are not fully understood. Another concern is that infection with Plasmodium falciparum, which causes the most severe form of the disease in young children and pregnant women, can lead to pathological inflammation resulting in severe complications, such as cerebral malaria. Thus, to succeed in developing an effective vaccine against malaria, it is crucial that the mechanisms underlying protective immunity as well as those that drive pathogenic responses are better understood.IL-23 is a proinflammatory cytokine that belongs to IL-12 cytokine family. It is a heterodimeric molecule composed of p40 and p19 subunits [3]. The proinflammatory activities of IL-23 are responsible for the onset not only of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis [4,5], but also infection-induced pathological consequences of infection with the pathogens causing Lyme disease and ...

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Escape of malaria parasites from host immunity requires CD4+CD25+ regulatory T cells

Cited by 316 publications

References 15 publications

Multiple functions of human T cells generated by experimental malaria challenge

Multiple functions of human T cells generated by experimental malaria challenge

Cutting Edge: IL-12 Induces CD4+CD25− T Cell Activation in the Presence of T Regulatory Cells

IL‐23 protection against Plasmodium berghei infection in mice is partially dependent on IL‐17 from macrophages

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