Effector Phenotype of<i>Plasmodium falciparum</i>–Specific CD4<sup>+</sup>T Cells Is Influenced by Both Age and Transmission Intensity in Naturally Exposed Populations

Boyle, Michelle J.; Jagannathan, Prasanna; Bowen, Katherine; McIntyre, Tara I.; Vance, Hilary M.; Farrington, Lila; Greenhouse, Bryan; Nankya, Felistas; Rek, John; Katureebe, Agaba; Arinaitwe, Emmanuel; Dorsey, Grant; Kamya, Moses R.; Feeney, Margaret E.

doi:10.1093/infdis/jiv054

Cited by 33 publications

(48 citation statements)

References 46 publications

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“…Additional studies using multiparameter flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) from asymptomatic children with higher exposures revealed a skewness towards an immune‐regulatory effector phenotype of CD4 + T cells 106. A higher proportion of CD4 + T cells that produce IL‐10 and coproduce IFN‐ γ and IL‐10 were observed in children from the high‐transmission area, whereas CD4 + T cells of children from the low‐transmission area predominantly produced IFN‐ γ , TNF‐ α and/or IL‐2, suggesting increased inflammatory responses in children at low exposure levels 56, 106.…”

Section: Reduced Inflammation: a Potential Parasite Tolerance Mechanimentioning

confidence: 99%

“…A higher proportion of CD4 + T cells that produce IL‐10 and coproduce IFN‐ γ and IL‐10 were observed in children from the high‐transmission area, whereas CD4 + T cells of children from the low‐transmission area predominantly produced IFN‐ γ , TNF‐ α and/or IL‐2, suggesting increased inflammatory responses in children at low exposure levels 56, 106. Similarly, CD4 + T cells from children with ≥ 2 prior episodes of malaria also coproduced IFN‐ γ and IL‐10 after stimulation with infected RBCs (iRBCs), whereas CD4 + T cells from children with fewer than two prior malaria episodes produced TNF‐ α only, without the co‐production of IL‐10,107 also demonstrating the predisposition towards an inflammatory state in children with fewer exposure histories.…”

Section: Reduced Inflammation: a Potential Parasite Tolerance Mechanimentioning

confidence: 99%

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Evaluating antidisease immunity to malaria and implications for vaccine design

Ademolue

Awandare

2017

Immunology

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SummaryImmunity to malaria could be categorized broadly as antiparasite or antidisease immunity. While most vaccine research efforts have focused on antiparasite immunity, the evidence from endemic populations suggest that antidisease immunity is an important component of natural immunity to malaria. The processes that mediate antidisease immunity have, however, attracted little to no attention, and most interests have been directed towards the antibody responses. This review evaluates the evidence for antidisease immunity in endemic areas and discusses the possible mechanisms responsible for it. Given the key role that inflammation plays in the pathogenesis of malaria, regulation of the inflammatory response appears to be a major mechanism for antidisease immunity in naturally exposed individuals.

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Section: Reduced Inflammation: a Potential Parasite Tolerance Mechanimentioning

confidence: 99%

Section: Reduced Inflammation: a Potential Parasite Tolerance Mechanimentioning

confidence: 99%

Evaluating antidisease immunity to malaria and implications for vaccine design

Ademolue

Awandare

2017

Immunology

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“…By using PBMC samples collected from Timika, Indonesia, where 125 million people live in malaria-endemic regions 323 , we found that IL-10 production was dependent on type I IFN's, post Contrastingly, in a high transmission setting, children have higher frequencies of parasite-specific CD4 + T cells producing IL-10, whereas the CD4 + T cells in adults produce IFNγ and TNF 48 .…”

Section: Discussionmentioning

confidence: 85%

“…While γδ T cells have been shown to produce IFNγ in response to parasite antigen, they were greatly outnumbered by αβ T cells 55 and this was observed in our studies (Fig 4 b). Earlier studies have shown CD4 + T cells to be a predominant source of IFNγ in response to parasite antigen 48,55,56 . While the contribution to IFNγ production by CD4 + and CD8 + T cells was relatively equal, CD4 + T cells were the main producers of IFNγ in response to parasite antigen 14 days post challenge (Fig 4c).…”

Section: Cd4 + T Cells Are the Predominant Source Of Ifnγ During Bloomentioning

confidence: 99%

“…More recently, it was shown that Tr1 cells emerge as the dominant CD4 + T cell response in highly exposed children living in malaria endemic regions 47,48,232 . The gating strategy for Tr1 cells, in our CHMI studies is shown in Fig 9. Similar to field studies, in our CHMI studies, we found a significant increase in IL-10 production by PBMC's in response to parasite antigen throughout the course of infection (Fig 10a).…”

Section: First Exposure To P Falciparum Induces Parasite-specific Trmentioning

confidence: 99%

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Regulation of CD4+ T cell responses during parasitic infections

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observed a significant increase in TNF producing CD4 + T cells in the T cell specific Blimp1 deficient mice which was associated with extensive splenomegaly, a characteristic feature observed in patients with visceral leishmaniasis (VL). Importantly, Blimp1 transcripts were also found to be up-regulated in VL patients, indicating the clinical relevance of Blimp1 during infection. We sought to determine the mechanism by which Blimp1 was regulating pathology in the spleen. Firstly, we confirmed that the loss of MZM's in the T cell specific Blimp1 deficient mice was due to a lack of IL-10, where T cell-specific IL-10 deficient mice also displayed the same phenotype of MZM loss, and this process appeared to be TNF dependent. In support of IL-10 mediating protection against MZM loss, we were able to show that IL-10 signalling in T cells and myeloid-derived populations was a requirement for protection against TNF-mediated destruction. In summary, our data reveals a novel mechanism where Blimp1 induced IL-10 production by Tr1 cells limits pathology during infection. These findings have wider implications for other inflammatory diseases. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School.I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis.

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A novel population of memory‐activated natural killer cells associated with low parasitaemia in Plasmodium falciparum‐exposed sickle‐cell trait children

et al. 2020

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Objectives. The sickle-cell trait phenotype is associated with protection from malaria. Multiple molecular mechanisms have been proposed to explain this protection, but the role of the host immune system has been poorly investigated. We hypothesised that cellular immunity to malaria may develop differently in sicklecell trait children (HbAS) and children with normal haemoglobin (HbAA) repeatedly exposed to Plasmodium falciparum (Pf). Methods. Paired samples collected prior to the Pf transmission season and during the first malaria episode of the ensuing transmission season from HbAS and HbAA children were analysed by multiplex bead-based assay and comprehensive multidimensional flow cytometry profiling. Results. Cellular immune profiles were enriched in HbAS relative to HbAA children before the start of the Pf transmission season, with a distinct NK subset. These cells were identified as a novel subset of memory-activated NK cells characterised by reduced expression of the ecto-enzyme CD38 as well as co-expression of high levels of HLA-DR and CD45RO. The frequency of this NK subset before the transmission season was negatively correlated with parasite density quantified during the first malaria episode of the ensuing transmission season. Functional assessment revealed that these CD38 dim CD45RO + HLA-DR + NK cells represent a important source of IFN-c. Conclusion. Our data suggest that this novel memory-activated NK cell subset may contribute to an accelerated and enhanced IFN-cmediated immune response and to control of parasite density in individuals with the sickle-cell trait. This distinct cellular immune profile may contribute to predispose HbAS children to a relative protection from malaria.

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Effector Phenotype ofPlasmodium falciparum–Specific CD4⁺T Cells Is Influenced by Both Age and Transmission Intensity in Naturally Exposed Populations

Abstract: These findings highlight major differences in the CD4(+) T-cell response of immune adults and nonimmune children that may be relevant for immune protection from malaria.

Cited by 33 publications

References 46 publications

Evaluating antidisease immunity to malaria and implications for vaccine design

Evaluating antidisease immunity to malaria and implications for vaccine design

Regulation of CD4+ T cell responses during parasitic infections

A novel population of memory‐activated natural killer cells associated with low parasitaemia in Plasmodium falciparum‐exposed sickle‐cell trait children

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Effector Phenotype ofPlasmodium falciparum–Specific CD4+T Cells Is Influenced by Both Age and Transmission Intensity in Naturally Exposed Populations

Abstract: These findings highlight major differences in the CD4(+) T-cell response of immune adults and nonimmune children that may be relevant for immune protection from malaria.

Cited by 33 publications

References 46 publications

Evaluating antidisease immunity to malaria and implications for vaccine design

Evaluating antidisease immunity to malaria and implications for vaccine design

Regulation of CD4+ T cell responses during parasitic infections

A novel population of memory‐activated natural killer cells associated with low parasitaemia in Plasmodium falciparum‐exposed sickle‐cell trait children

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Product

Resources

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Effector Phenotype ofPlasmodium falciparum–Specific CD4⁺T Cells Is Influenced by Both Age and Transmission Intensity in Naturally Exposed Populations