CD4 T Cell Responses to a Variant Antigen of the Malaria Parasite<i>Plasmodium falciparum,</i>Erythrocyte Membrane Protein–1, in Individuals Living in Malaria‐Endemic Areas

Allsopp, Catherine E. M.; Sanni, Latifu A.; Reubsaet, Lieke; Ndungu, Francis M.; Newbold, Chris; Mwangi, Tabitha; Marsh, Kevin; Langhorne, Jean

doi:10.1086/339521

Cited by 19 publications

(20 citation statements)

References 32 publications

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“…Seventeen and 16 of 33 donors were positive for IFN-␥ and IL-10 production, respectively. As described previously (20), there was generally an inverse or no association between IL-10 production and CD4 T cell proliferation. Interestingly, some individuals responded by IFN-␥ production and no cell division, and we observed an unexpected positive association between IFN-␥ and IL-10 concentrations (Spearman's coefficient ϭ 0.62, p ϭ 0001, data not shown).…”

Section: Assessment Of Cd4 T Cell Division and Cytokine Production Insupporting

confidence: 71%

“…Two recombinant protein fragments of PfEMP-1 were expressed and purified as described elsewhere (20). CIDR1-␣ was obtained from a PfEMP-1 gene of the Malayan Camp laboratory isolate of P. falciparum (GenBank accession no.…”

Section: Preparation and Purification Of Pfemp-1 Fragmentsmentioning

confidence: 99%

“…PBMC were isolated as described previously (20). Blood was diluted 1/2 in RPMI 1640 without additives, and purified over Lymphoprep (Nycomed) by centrifugation at 800 ϫ g for 20 min.…”

Section: Isolation Of Pbmc From Whole Bloodmentioning

confidence: 99%

“…Candidate membrane-bound molecules are the variable surface Ags (VSA), which include those encoded by the var multigene family, such as P. falciparum erythrocyte membrane protein-1 (PfEMP-1). Interestingly, the cysteine interdomain region-1␣ (CIDR-1␣) domain of PfEMP-1 has been shown to stimulate CD4 T cells from both exposed and nonexposed individuals (20). The CIDR-1␣ domain of PfEMP-1, which binds to CD36 (21), is thought to play a role in the adhesion of iRBC to the host endothelium (22,23).…”

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confidence: 99%

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CD4 T Cells from Malaria-Nonexposed Individuals Respond to the CD36-Binding Domain ofPlasmodium falciparumErythrocyte Membrane Protein-1 via an MHC Class II-TCR-Independent Pathway

Ndungu

Sanni

Urban

et al. 2006

The Journal of Immunology

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We have studied the human CD4 T cell response to a functionally conserved domain of Plasmodium falciparum erythrocyte membrane protein-1, cysteine interdomain region-1α (CIDR-1α). Responses to CIDR-1α were striking in that both exposed and nonexposed donors responded. The IFN-γ response to CIDR-1α in the nonexposed donors was partially independent of TCR engagement of MHC class II and peptide. Contrastingly, CD4 T cell and IFN-γ responses in malaria-exposed donors were MHC class II restricted, suggesting that the CD4 T cell response to CIDR-1α in malaria semi-immune adults also has a TCR-mediated component, which may represent a memory response. Dendritic cells isolated from human peripheral blood were activated by CIDR-1α to produce IL-12, IL-10, and IL-18. IL-12 was detectable only between 6 and 12 h of culture, whereas the IL-10 continued to increase throughout the 24-h time course. These data strengthen previous observations that P. falciparum interacts directly with human dendritic cells, and suggests that the interaction between CIDR-1α and the host cell may be responsible for regulation of the CD4 T cell and cytokine responses to P. falciparum-infected erythrocytes reported previously.

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Section: Assessment Of Cd4 T Cell Division and Cytokine Production Insupporting

confidence: 71%

Section: Preparation and Purification Of Pfemp-1 Fragmentsmentioning

confidence: 99%

“…PBMC were isolated as described previously (20). Blood was diluted 1/2 in RPMI 1640 without additives, and purified over Lymphoprep (Nycomed) by centrifugation at 800 ϫ g for 20 min.…”

Section: Isolation Of Pbmc From Whole Bloodmentioning

confidence: 99%

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confidence: 99%

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CD4 T Cells from Malaria-Nonexposed Individuals Respond to the CD36-Binding Domain ofPlasmodium falciparumErythrocyte Membrane Protein-1 via an MHC Class II-TCR-Independent Pathway

Ndungu

Sanni

Urban

et al. 2006

The Journal of Immunology

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“…The knowledge of B-and T-cell activity directed to specific epitopes of PfEMP1 in naturally exposed humans is very limited (1), and no studies have reported PfEMP1-specific immune responses in the cord blood from neonates born to mothers with malaria. Epidemiological studies suggest that pregnancy-associated malaria increases the likelihood of early infection in the newborn (6,18), possibly as a result of antigen exposure inducing immunosuppressive pathways during fetal development (2,3).…”

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confidence: 99%

Neonatal and Maternal Immunological Responses to Conserved Epitopes within the DBL-γ3 Chondroitin Sulfate A-Binding Domain ofPlasmodium falciparumErythrocyte Membrane Protein 1

et al. 2005

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Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates the adherence of P. falciparuminfected erythrocytes to placental syncytiotrophoblasts via interactions with chondroitin sulfate A (CSA), a characteristic of pregnancy-associated malaria. Pregnancy-associated malaria predicts increased susceptibility of newborns to malaria, and it is postulated that transplacental passage of parasite antigen induces immune regulatory activity in the neonate. We wished to examine the immune responsiveness to a CSA-binding domain of PfEMP1, the DBL-␥3 domain, in cord and maternal venous blood obtained from pregnancies with various histories of P. falciparum infection. We assessed in vitro T-cell cytokine and plasma immunoglobulin G (IgG) and IgM responses to four peptides corresponding to highly conserved regions of a DBL-␥3 domain common to central African parasite isolates. The presence of placental P. falciparum infection at delivery was associated with elevated frequencies of DBL-␥3 peptide-specific CD3 ؉ interleukin-10-positive T cells in cord blood, while treatment and clearance of infection prior to delivery was associated with elevated frequencies of CD3؉ gamma interferon-positive T cells. DBL-␥3 peptide-specific IgM antibodies were detected in 12 of 60 (20%) cord plasma samples from those born to mothers with P. falciparum infection during pregnancy. Consistent with polyclonal anti-PfEMP1 antibody responses that are associated with protection against pregnancy-associated malaria, the presence of maternal IgG antibodies with specificity for one of the DBL-␥3 peptides showed a parity-dependent profile. These data demonstrate that peptides corresponding to conserved regions of the DBL-␥3 domain of PfEMP1 are immunogenic in P. falciparum-infected mothers and their offspring.

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Surface antigens of Plasmodium falciparum-infected erythrocytes as immune targets and malaria vaccine candidates

Chan

Fowkes

Beeson

2014

Cell. Mol. Life Sci.

140

147

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Understanding the targets and mechanisms of human immunity to malaria caused by Plasmodium falciparum is crucial for advancing effective vaccines and developing tools for measuring immunity and exposure in populations. Acquired immunity to malaria predominantly targets the blood stage of infection when merozoites of Plasmodium spp. infect erythrocytes and replicate within them. During the intra-erythrocytic development of P. falciparum, numerous parasite-derived antigens are expressed on the surface of infected erythrocytes (IEs). These antigens enable P. falciparum-IEs to adhere in the vasculature and accumulate in multiple organs, which is a key process in the pathogenesis of disease. IE surface antigens, often referred to as variant surface antigens, are important targets of acquired protective immunity and include PfEMP1, RIFIN, STEVOR and SURFIN. These antigens are highly polymorphic and encoded by multigene families, which generate substantial antigenic diversity to mediate immune evasion. The most important immune target appears to be PfEMP1, which is a major ligand for vascular adhesion and sequestration of IEs. Studies are beginning to identify specific variants of PfEMP1 linked to disease pathogenesis that may be suitable for vaccine development, but overcoming antigenic diversity in PfEMP1 remains a major challenge. Much less is known about other surface antigens, or antigens on the surface of gametocyte-IEs, the effector mechanisms that mediate immunity, and how immunity is acquired and maintained over time; these are important topics for future research.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-014-1614-3) contains supplementary material, which is available to authorized users.

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CD4 T Cell Responses to a Variant Antigen of the Malaria ParasitePlasmodium falciparum,Erythrocyte Membrane Protein–1, in Individuals Living in Malaria‐Endemic Areas

Cited by 19 publications

References 32 publications

CD4 T Cells from Malaria-Nonexposed Individuals Respond to the CD36-Binding Domain ofPlasmodium falciparumErythrocyte Membrane Protein-1 via an MHC Class II-TCR-Independent Pathway

CD4 T Cells from Malaria-Nonexposed Individuals Respond to the CD36-Binding Domain ofPlasmodium falciparumErythrocyte Membrane Protein-1 via an MHC Class II-TCR-Independent Pathway

Neonatal and Maternal Immunological Responses to Conserved Epitopes within the DBL-γ3 Chondroitin Sulfate A-Binding Domain ofPlasmodium falciparumErythrocyte Membrane Protein 1

Surface antigens of Plasmodium falciparum-infected erythrocytes as immune targets and malaria vaccine candidates

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