V 9V 2 T-Cell Anergy and Complementarity-Determining Region 3-Specific Depletion during Paroxysm of Nonendemic Malaria Infection (original) (raw)
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Journal of Allergy and Clinical Immunology, 1996
T Iymphocytes that express T-cell receptors encoded by the 7 and 8 T-cell receptor genes (78 T cells), and preferentially those expressing the V79 and V82 gene segments, are activated by microbial and parasitic organisms in vitro and have been implicated in the pathogenesis of the fever and rigors during acute malaria. We have found, in a cohort of nine nonimmune patients who contracted malaria during travel to endemic areas (five with Plasmodium falciparum and four with P. vivax infections) that 78 T lymphocytes expanded to comprise 17. 92% +-11% of the peripheral blood mononuclear cells (vs 3. 08% +-2. 4% 78 cells in normal control subjects). Although V82 + cells predominated among the 78 subset, 78 lymphocytes expressing the V81 gene segment also expanded significantly in some patients. Importantly, the 78 cells continued to expand for 2 months after the injection, and the mean level of y8 cells peaked during the second month after the acute clinical syndrome, when patients were free of symptoms. Thus although 78 T cells may contribute to the pathogenesis of the acute clinical syndrome, our findings suggest that 78 lymphocytes could also play a role in generating an immune response to plasmodia. (J Allergy Clin Immunol 1996;97:1387-92.) Human malaria is a tropical parasitic disease afflicting over 400 million individuals worldwide, and it is caused by four Plasmodium species: P. vivax, P. ovale, P. malariae, and the malignant form, P. falciparum. 1 Infections with P. falciparum are responsible for over 1 × 106 deaths annually, and the other forms of malaria are responsible for significant morbidity in developing nations? The nature of the clinical response to Plasmodium infection is complex: infected individuals residing in endemic areas develop immunity during the first few years of life, and repeated infections in adulthood result in minimal clinical symptoms. 2 In contrast, individuals from nonendemic areas respond to infections with an acute febrile syndrome and may die during the acute episode. Both B-cell
Scientific Reports
Vδ2 + γδ T cells are semi-innate T cells that expand markedly following P. falciparum (Pf) infection in naïve adults, but are lost and become dysfunctional among children repeatedly exposed to malaria. The role of these cells in mediating clinical immunity (i.e. protection against symptoms) to malaria remains unclear. We measured Vδ2 + T cell absolute counts at acute and convalescent malaria timepoints (n = 43), and Vδ2 + counts, cellular phenotype, and cytokine production following in vitro stimulation at asymptomatic visits (n = 377), among children aged 6 months to 10 years living in Uganda. Increasing age was associated with diminished in vivo expansion following malaria, and lower Vδ2 absolute counts overall, among children living in a high transmission setting. Microscopic parasitemia and expression of the immunoregulatory markers Tim-3 and CD57 were associated with diminished Vδ2 + T cell pro-inflammatory cytokine production. Higher Vδ2 pro-inflammatory cytokine production was associated with protection from subsequent Pf infection, but also with an increased odds of symptoms once infected. Vδ2 + T cells may play a role in preventing malaria infection in children living in endemic settings; progressive loss and dysfunction of these cells may represent a disease tolerance mechanism that contributes to the development of clinical immunity to malaria. Despite declines in malaria morbidity in parts of sub-Saharan Africa 1 , malaria causes hundreds of thousands of deaths annually, predominantly among young children 1, 2. Children residing in endemic areas eventually acquire 'clinical' immunity to malaria (i.e. they are protected against symptoms) 3-5 , but they commonly harbor parasites as asymptomatic and transmitting carriers 6, 7. Although individuals generally do not appear to develop sterilizing immunity that prevents any infection, blood-stage parasite density declines with age and repeated exposure 8 , suggesting the development of immune responses that are able to limit blood stage replication. Importantly, pro-inflammatory responses that limit parasitemia may also lead to clinical symptoms; thus, 'clinical' immunity could depend upon the ability to down-modulate such responses, as suggested by recent data from our group and others 9-11. The Vγ9 Vδ2 subset of γδ T cells, which constitute 0.5 to 5% of peripheral T cells in humans, have been shown to robustly proliferate and produce pro-inflammatory cytokines in response to Pf antigen stimulation and to markedly expand following malaria infection in naïve hosts 12-17. These cells (hereafter termed Vδ2 T cells) rapidly react to phosphoantigens produced by the plasmodial apicoplast, and have been shown to inhibit parasite growth in vitro via the release of cytotoxic granules containing granulysin 18, 19. Given these attributes, Vδ2 T cells may
The Journal of infectious diseases, 2017
During Plasmodium falciparum infections, erythrocyte-stage parasites inhibit dendritic cell maturation and function, compromising effective antimalarial adaptive immunity. Human Vγ9Vδ2 T cells can act in vitro as antigen-presenting cells (APCs) and induce αβ T-cell activation. However, the relevance of this activity in vivo has remained elusive. Because Vγ9Vδ2 T cells are activated during the early immune response against P. falciparum infection, we investigated whether they could contribute to the instruction of adaptive immune responses toward malaria parasites. In P. falciparum-infected patients, Vγ9Vδ2 T cells presented increased surface expression of APC-associated markers HLA-DR and CD86. In response to infected red blood cells in vitro, Vγ9Vδ2 T cells upregulated surface expression of HLA-DR, HLA-ABC, CD40, CD80, CD83, and CD86, induced naive αβ T-cell responses, and cross- presented soluble prototypical protein to antigen-specific CD8+ T cells. Our findings qualify Vγ9Vδ2 T ...
Transient Increase in Circulating y/8 T Cells during Plasmodium vivax Malarial Paroxysms
2000
Summary The percentage of peripheral blood mononuclear cells (PBMC) bearing the CD3 § phenotype and the ot/~ and 3//8 T cell receptors (TCR) in PBMC were examined in Plasmodium vivax malaria patients and convalescents. The cells were labeled with monoclonal antibodies, stained with either fluorescene or phycoerythrin, and examined by ultraviolet (UV) microscopy. A highly significant increase in both the
The Journal of Immunology, 2001
γδ T cells are implicated to play crucial roles during early immune responses to pathogens. A subset of human γδ T cells carrying the Vγ9Vδ2 TCR recognize small, phosphorylated nonpeptidic Ags. However, the precise role of these cells and the ligands recognized in human immune responses against pathogens remains unclear because of the lack of suitable animal models. We have analyzed the reactivity of spleen cells of the New World monkey Aotus nancymaae against isopentenyl pyrophosphate (IPP), a phosphorylated microbial metabolite selectively activating Vγ9Vδ2 T cells. Spleen cells were stimulated by IPP and the expanding cell population expressed the Vγ9 TCR. TRGV-J and TRDV-D-J rearrangements expressed by IPP-stimulated cells of Aotus were analyzed by RT-PCR and DNA sequencing. The TRGV-J and TRDV-D-J rearrangements expressed by IPP-stimulated Aotus and human γδ T cells were similar with respect to 1) TCR gene segment usage, 2) a high degree of germline sequence homology of the TCR...
Infection and Immunity, 2001
␥␦ T cells have variously been implicated in the protection against, and the pathogenesis of, malaria, but few studies have examined the ␥␦ T-cell response to malaria in African children, who suffer the large majority of malaria-associated morbidity and mortality. This is unfortunate, since available data suggest that simple extrapolation of conclusions drawn from studies of nonimmune adults ex vivo and in vitro is not always possible. Here we show that both the frequencies and the absolute numbers of ␥␦ T cells are transiently increased following treatment of Plasmodium falciparum malaria in Ghanaian children and they can constitute 30 to 50% of all T cells shortly after initiation of antimalarial chemotherapy. The bulk of the ␥␦ T cells involved in this perturbation expressed V␦1 and had a highly activated phenotype. Analysis of the T-cell receptors (TCR) of the V␦1 ؉ cell population at the peak of their increase showed that all expressed V␥ chains were used, and CDR3 length polymorphism indicated that the expanded V␦1 population was highly polyclonal. A very high proportion of the V␦1 ؉ T cells produced gamma interferon, while fewer V␦1 ؉ cells than the average proportion of all CD3 ؉ cells produced tumor necrosis factor alpha. No interleukin 10 production was detected among TCR-␥␦ ؉ cells in general or V␦1 ؉ cells in particular. Taken together, our data point to an immunoregulatory role of the expanded V␦1 ؉ T-cell population in this group of semi-immune P. falciparum malaria patients.
Infection and Immunity, 2015
Malaria induces potent activation and expansion of the Vγ9Vδ2 subpopulation of γδT cells, which inhibit thePlasmodium falciparumblood cycle through soluble cytotoxic mediators, abrogating merozoite invasion capacity. Intraerythrocytic stages efficiently trigger Vγ9Vδ2 T-cell activation and degranulation through poorly understood mechanisms.P. falciparumblood-stage extracts are known to contain phosphoantigens able to stimulate Vγ9Vδ2 T cells, but how these are presented by intact infected red blood cells (iRBCs) remains elusive. Here we show that, unlike activation by phosphoantigen-expressing cells, Vγ9Vδ2 T-cell activation by intact iRBCs is independent of butyrophilin expression by the iRBC, and contact with an intact iRBC is not required. Moreover, blood-stage culture supernatants proved to be as potent activators of Vγ9Vδ2 T cells as iRBCs. Bioactivity in the microenvironment is attributable to phosphoantigens, as it is dependent on the parasite DOXP pathway, on Vγ9Vδ2 TCR sign...
The response of γδ T cells in malaria infections: a hypothesis
Research in Immunology, 1994
Cell-mediated immunity to the asexual blood stages of malarial parasites: animal models. Immunol. Len.. 25, 87-96. Zhang, J.H. (1990), Human macrophage activation by direct contact with stimulated T cells: role of accessory molecules and membrane bound cytokines. Thesis no. 9212, p. 43, Library of the
Infection and Immunity, 2015
Malaria induces potent activation and expansion of the Vγ9Vδ2 subpopulation of γδT cells, which inhibit the Plasmodium falciparum blood cycle through soluble cytotoxic mediators, abrogating merozoite invasion capacity. Intraerythrocytic stages efficiently trigger Vγ9Vδ2 T-cell activation and degranulation through poorly understood mechanisms. P. falciparum blood-stage extracts are known to contain phosphoantigens able to stimulate Vγ9Vδ2 T cells, but how these are presented by intact infected red blood cells (iRBCs) remains elusive. Here we show that, unlike activation by phosphoantigen-expressing cells, Vγ9Vδ2 T-cell activation by intact iRBCs is independent of butyrophilin expression by the iRBC, and contact with an intact iRBC is not required. Moreover, blood-stage culture supernatants proved to be as potent activators of Vγ9Vδ2 T cells as iRBCs. Bioactivity in the microenvironment is attributable to phosphoantigens, as it is dependent on the parasite DOXP pathway, on Vγ9Vδ2 TCR ...