Immunosuppression in Children With Malaria

Greenwood, Brian; Palit, A.; Bradley-Moore, AliceM.; Bryceson, A.

doi:10.1016/s0140-6736(72)90569-7

Cited by 245 publications

(125 citation statements)

References 9 publications

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“…These findings are consistent with the concept that IL-2 consumption by natural Treg cells may contribute to their suppressive effects and result in apoptosis of target T cells (45,46). Although the exact mechanism is unclear, consumption of IL-2 by expanding natural Treg cells may play a previously unrecognized role in immunosuppression associated with blood-stage malaria in humans as well as in mice (23,(47)(48)(49)(50).…”

Section: Discussionsupporting

confidence: 88%

IL-2 Contributes to Maintaining a Balance between CD4+Foxp3+ Regulatory T Cells and Effector CD4+ T Cells Required for Immune Control of Blood-Stage Malaria Infection

Berretta

St-Pierre

Piccirillo

et al. 2011

The Journal of Immunology

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To investigate the role of CD4+CD25+Foxp3+ regulatory T (Treg) cells in blood-stage malaria, we compared Plasmodium chabaudi AS infection in wild-type (WT) C57BL/6 and transgenic mice overexpressing the transcription factor Foxp3 (Foxp3Tg) and observed that Foxp3Tg mice experienced lethal infection and deficient malaria-specific immune responses. Adoptive transfer of total CD4+ T cells from Foxp3Tg mice or CD4+CD25+ T cells from WT mice to naive WT recipients confirmed that high numbers of Treg cells compromised immune control of malaria. Transfer of GFP+CD4+CD25+ T cells to naive WT recipients together with immunohistochemical staining of spleens from infected WT mice demonstrated that Foxp3+ Treg cells localized in the T cell area of the spleen. Determination of CD4+Foxp3+ Treg cell responses in the spleen of infected WT mice revealed a significant but transient increase in CD4+Foxp3+ Treg cells early in infection. This was followed by a significant and sustained decrease due to reduced proliferation and apoptosis of CD4+Foxp3+ Treg cells. Importantly, the kinetics of IL-2 secretion by effector CD4+Foxp3− T cells coincided with changes in CD4+Foxp3+ cells and the differentiation of CD4+T-bet+IFN-γ+ cells required for immune control of infection. Administration of the IL-2/anti–IL-2 mAb (clone JES6-1) complex to infected WT mice increased the severity of P. chabaudi AS infection and promoted expansion of Foxp3+ Treg cells. Collectively, these data demonstrate that the ability to control and eliminate P. chabaudi AS infection is due to a tight balance between natural Treg cells and effector CD4+ Th1 cells, a balance regulated in part by IL-2.

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Section: Discussionsupporting

confidence: 88%

IL-2 Contributes to Maintaining a Balance between CD4+Foxp3+ Regulatory T Cells and Effector CD4+ T Cells Required for Immune Control of Blood-Stage Malaria Infection

Berretta

St-Pierre

Piccirillo

et al. 2011

The Journal of Immunology

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“…Indeed, in one particular study volunteers were immunized with low doses of Plasmodium-infected RBC (iRBC), and they produced T-cell IFN-g responses against blood-stage Ag that were associated with protection from challenge in the absence of Ab responses [7]. A frequently described observation is the apparently short-lived immunity generated after exposure to the parasite [8,9], which may be a result of depressed cellular immunity [10,11]. We have recently shown that recipients of experimental malaria vaccines in Kenya had decreased T-cell responses against the vaccine Ag when parasitemic at the time of vaccination [12].…”

Section: Introductionmentioning

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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“…A number of epidemiological studies suggest the existence of malaria-induced immune suppression. In endemic areas, an association of malaria with a higher incidence of other infectious diseases [3][4][5] and reduced immune responses to vaccination during malaria infections [6,7] is found.…”

Section: Introductionmentioning

confidence: 99%

Role of TGF‐β and PGE₂in T cell responses during Plasmodium yoelii infection

et al. 2007

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During an acute blood-stage malaria infection, T cell responses to malaria and other bystander antigens are inhibited. Plasmodium infection induces strong cytokine responses that facilitate parasite clearance but may interfere with T cell functions, as some of the soluble immune mediators induced are also general inhibitors of T cell responses. Using a malaria mouse model, we have analyzed the cytokines produced by dendritic cells in response to P. yoelii infection that have potential T cell inhibitory activity. We found that during acute infection DC migrate to the spleen and secrete TGF-b, prostaglandin E 2 (PGE 2 ) and IL-10. We have analyzed the role of these general T cell inhibitors in a particular T cell response of evident importance in malaria infections: the CD8 + T cells generated against the liver-stage of the disease. During blood-stage infection, inhibition of the activity of TGF-b and PGE 2 restores the CD8 + T cell responses generated by sporozoites, increasing protection against re-infection. Our findings suggest that the strong cytokine response induced by blood-stage P. yoelii infection affects host T cell responses, inhibiting protective CD8 + T cells against the liver-stage of the disease.

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Immunosuppression in Children With Malaria

Cited by 245 publications

References 9 publications

IL-2 Contributes to Maintaining a Balance between CD4+Foxp3+ Regulatory T Cells and Effector CD4+ T Cells Required for Immune Control of Blood-Stage Malaria Infection

IL-2 Contributes to Maintaining a Balance between CD4+Foxp3+ Regulatory T Cells and Effector CD4+ T Cells Required for Immune Control of Blood-Stage Malaria Infection

Multiple functions of human T cells generated by experimental malaria challenge

Role of TGF‐β and PGE₂in T cell responses during Plasmodium yoelii infection

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Immunosuppression in Children With Malaria

Cited by 245 publications

References 9 publications

IL-2 Contributes to Maintaining a Balance between CD4+Foxp3+ Regulatory T Cells and Effector CD4+ T Cells Required for Immune Control of Blood-Stage Malaria Infection

IL-2 Contributes to Maintaining a Balance between CD4+Foxp3+ Regulatory T Cells and Effector CD4+ T Cells Required for Immune Control of Blood-Stage Malaria Infection

Multiple functions of human T cells generated by experimental malaria challenge

Role of TGF‐β and PGE2 in T cell responses during Plasmodium yoelii infection

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Product

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Role of TGF‐β and PGE₂in T cell responses during Plasmodium yoelii infection