Abstract:Naturally acquired immunity to Plasmodium falciparum malaria in malaria holoendemic areas is characterized by the gradual, age-related development of protection against high-density parasitemia and clinical malaria. Animal studies, and less commonly, observations of humans with malaria, suggest that T-cell responses are important in the development and maintenance of this immunity, which is mediated primarily by antibodies that slow repeated cycles of merozoites through erythrocytes. To advance our rather limi… Show more
“…In the individual depicted here, clear CD8 ϩ T-cell populations are observed for all specificities with the exception of YLL. (40,41). This is consistent with the recent description of stem cell-like memory T cells, which express many other surface markers typically associated with antigen-inexperienced naïve cells and likely represent a very early stage of memory T-cell differentiation (42).…”
Section: Distinct Phenotypes Characterize Different Ebv-derived Epitosupporting
e Coinfection with Plasmodium falciparum malaria and Epstein-Barr virus (EBV) is a major risk factor for endemic Burkitt lymphoma (eBL), still one of the most prevalent pediatric cancers in equatorial Africa. Although malaria infection has been associated with immunosuppression, the precise mechanisms that contribute to EBV-associated lymphomagenesis remain unclear. In this study, we used polychromatic flow cytometry to characterize CD8 ؉ T-cell subsets specific for EBV-derived lytic (BMFL1 and BRLF1) and latent (LMP1, LMP2, and EBNA3C) antigens in individuals with divergent malaria exposure. No malaria-associated differences in EBV-specific CD8 ؉ T-cell frequencies were observed. However, based on a multidimensional analysis of CD45RO, CD27, CCR7, CD127, CD57, and PD-1 expression, we found that individuals living in regions with intense and perennial (holoendemic) malaria transmission harbored more differentiated EBV-specific CD8 ؉ T-cell populations that contained fewer central memory cells than individuals living in regions with little or no (hypoendemic) malaria. This profile shift was most marked for EBV-specific CD8؉ T-cell populations that targeted latent antigens. Importantly, malaria exposure did not skew the phenotypic properties of either cytomegalovirus (CMV)-specific CD8 ؉ T cells or the global CD8 ؉ memory T-cell pool. These observations define a malaria-associated aberration localized to the EBV-specific CD8 ؉ T-cell compartment that illuminates the etiology of eBL.
“…In the individual depicted here, clear CD8 ϩ T-cell populations are observed for all specificities with the exception of YLL. (40,41). This is consistent with the recent description of stem cell-like memory T cells, which express many other surface markers typically associated with antigen-inexperienced naïve cells and likely represent a very early stage of memory T-cell differentiation (42).…”
Section: Distinct Phenotypes Characterize Different Ebv-derived Epitosupporting
e Coinfection with Plasmodium falciparum malaria and Epstein-Barr virus (EBV) is a major risk factor for endemic Burkitt lymphoma (eBL), still one of the most prevalent pediatric cancers in equatorial Africa. Although malaria infection has been associated with immunosuppression, the precise mechanisms that contribute to EBV-associated lymphomagenesis remain unclear. In this study, we used polychromatic flow cytometry to characterize CD8 ؉ T-cell subsets specific for EBV-derived lytic (BMFL1 and BRLF1) and latent (LMP1, LMP2, and EBNA3C) antigens in individuals with divergent malaria exposure. No malaria-associated differences in EBV-specific CD8 ؉ T-cell frequencies were observed. However, based on a multidimensional analysis of CD45RO, CD27, CCR7, CD127, CD57, and PD-1 expression, we found that individuals living in regions with intense and perennial (holoendemic) malaria transmission harbored more differentiated EBV-specific CD8 ؉ T-cell populations that contained fewer central memory cells than individuals living in regions with little or no (hypoendemic) malaria. This profile shift was most marked for EBV-specific CD8؉ T-cell populations that targeted latent antigens. Importantly, malaria exposure did not skew the phenotypic properties of either cytomegalovirus (CMV)-specific CD8 ؉ T cells or the global CD8 ؉ memory T-cell pool. These observations define a malaria-associated aberration localized to the EBV-specific CD8 ؉ T-cell compartment that illuminates the etiology of eBL.
“…Less is known about the role of T cells in human malaria infections. Recently, age-related qualitative differences in the T cell response to merozoite surface protein 1 were shown, which may contribute to age-related malarial immunity (10). Further investigation in the role of T cells in protection from severe disease in humans is needed.…”
Infection with Plasmodium falciparum can lead to a range of severe to minimal symptoms, occasionally resulting in death in young children or nonimmune adults. In areas of high transmission, older children and adults generally suffer only mild or asymptomatic malaria infections and rarely develop severe disease. The immune features underlying this apparent immunity to severe disease remain elusive. To gain insight into host responses associated with severe and mild malaria, we conducted a longitudinal study of five children who first presented with severe malaria and, 1 month later, with mild malaria. Employing peripheral blood whole-genome profiling, we identified 68 genes that were associated with mild malaria compared to their expression in the severe malaria episode (paired Students t test, P < 0.05). These genes reflect the interferon (IFN) pathway and T cell biology and include IFN-induced protein transcripts 1 to 3, oligoadenylate synthetases 1 and 3, and the T cell markers cathepsin W and perforin. Gene set enrichment analysis identified Gene Ontology (GO) pathways associated with mild malaria to include the type I interferon-mediated signaling pathway (GO 0060337), T cell activation (GO 0042110), and other GO pathways representing many aspects of immune activation. In contrast, only six genes were associated with severe malaria, including thymidine kinase 1, which was recently found to be a biomarker of cerebral malaria susceptibility in the murine model, and carbonic anhydrase, reflecting the blood's abnormal acid base environment during severe disease. These data may provide potential insights to inform pathogenesis models and the development of therapeutics to reduce severe disease outcomes due to P. falciparum infection.
“…lood-stage malaria infection, like other chronic infections, generates effector memory T cells (Tem) in mice and humans (1,2). Children living in areas with high malaria transmission demonstrate a decrease in the incidence of malaria disease as they grow older (3).…”
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confidence: 99%
“…Children living in areas with high malaria transmission demonstrate a decrease in the incidence of malaria disease as they grow older (3). This decrease in malarial incidence is associated with an increased number of gamma interferon (IFN-␥)-producing effector/effector memory CD4 T cells upon parasite exposure (1,2). However, the levels of malaria-responsive T cells and malaria antigen-specific antibody titers decay over time (4)(5)(6), as does clinical immunity.…”
Exposure to blood-stage malaria infection is often persistent, leading to generation of CD4 effector and effector memory T cells that contribute to protection. We showed previously that chronic exposure to blood-stage Plasmodium chabaudi offers the best protection from parasitemia and pathology in reinfection cases, correlating with an increase in Th1 cells. Although much is known about the features of resting or exhausted memory T cells (Tmem), little is known about the functional capacities of chronically stimulated but protective T cells. To determine the functional capacity of CD4 T cells generated by chronic infection upon reexposure to parasite, we compared their responses to known features of classical Tmem. The numbers of cytokine-producing T cells increased following infection in the polyclonal populations, suggesting an increase in pathogen-specific T cells. Malaria antigen-specific B5 T cell receptor (TCR) transgenic (Tg) T cells from chronic infection proliferated on reinfection and were highly sensitive to TCR stimulation without costimulation, as shown for Tmem in acute stimulations. However, B5 Tmem did not accumulate more than naive B5 T cells in vivo or in vitro and became apoptotic. Failure to accumulate was partly the result of chronic stimulation, since eliminating persistent parasites before reinfection slightly increased the accumulation of B5 Tg T cells upon reinfection. The levels of specific gamma interferon-positive, interleukin-10-positive T cells, which protect animals from pathology, increased after malaria infection. These data demonstrate that although chronic infection generates a protective T cell population with increased TCR sensitivity and cytokine production, they do not reexpand upon reexposure due to increased apoptosis.
KEYWORDS T cells, immune memory, malaria, mouse
Blood-stage malaria infection, like other chronic infections, generates effector memory T cells (Tem) in mice and humans (1, 2). Children living in areas with high malaria transmission demonstrate a decrease in the incidence of malaria disease as they grow older (3). This decrease in malarial incidence is associated with an increased number of gamma interferon (IFN-␥)-producing effector/effector memory CD4 T cells upon parasite exposure (1, 2). However, the levels of malaria-responsive T cells and malaria antigen-specific antibody titers decay over time (4-6), as does clinical immunity. These data support the conclusion that there are disease-protective memory B and T cells in individuals repeatedly infected with malaria that decay in the absence of exposure. However, the effector mechanisms by which these immune cells contribute to protection from repeated parasitemia and malaria disease are poorly understood.
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