Phenotypic and functional profiling of malaria-induced CD8 and CD4 T cells during blood-stage infection with Plasmodium yoelii

Joint ICGEB-Emory Vaccine Center, Aruna Asaf Ali Marg, New Delhi, India.
Immunology (Impact Factor: 3.8). 10/2010; 132(2):273-86. DOI: 10.1111/j.1365-2567.2010.03363.x
Source: PubMed


It is widely accepted that antibodies and CD4 T cells play critical roles in the immune response during the blood stage of malaria, whereas the role of CD8 T cells remains controversial. Here, we show that both CD8 and CD4 T cells robustly responded to an acute self-limiting blood-stage infection with Plasmodium yoelii. Similar to antigen-specific T cells, both CD8 and CD4 T cells showed dynamic expression of the surface proteins interleukin (IL)-7R and programmed death-1 (PD-1). Additionally, activated CD8 T cells showed differences in the expression of Killer cell lectin-like receptor G1, L-selectin and B cell lymphoma-2 and produced granzyme B, indicating cytotoxic activity, and the initially high expression of T-box transcription factor TBX21 in malaria-activated CD4 T cells indicated an early T helper type 1 (Th1)-skewed immune response. Our data demonstrate that blood-stage malaria infection results in a striking T-cell response and that activated CD8 and CD4 T cells have phenotypic and functional characteristics that are consistent with conventional antigen-specific effector and memory T cells. Therefore, a better understanding of the CD8 and CD4 T-cell response induced by blood-stage infection may prove to be essential in the development of a vaccine that targets the erythrocytic stage of the malarial parasite.

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    • "One of the first studies to examine PD-1 expression during malaria used a mouse model to show PD-1 expression on IL-7Rlo-expressing CD4+ and CD8+ T cells (Chandele et al., 2011). These PD-1-expressing cells (especially CD8+ T cells) were almost completely lost within 30 days of infection (Chandele et al., 2011). The study did not however measure functional responses to identify T cell exhaustion. "
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    ABSTRACT: Malaria is a significant global burden but after >30 years of effort there is no vaccine on the market. While the complex life cycle of the parasite presents several challenges, many years of research have also identified several mechanisms of immune evasion by Plasmodium spp. Recent research on malaria, has investigated the programmed cell death-1 (PD-1) pathway which mediates exhaustion of T cells, characterized by poor effector functions and recall responses and in some cases loss of the cells by apoptosis. Such studies have shown exhaustion of CD4(+) T cells and an unappreciated role for CD8(+) T cells in promoting sterile immunity against blood stage malaria. This is because PD-1 mediates up to a 95% reduction in numbers and functional capacity of parasite-specific CD8(+) T cells, thus masking their role in protection. The role of T cell exhaustion during malaria provides an explanation for the absence of sterile immunity following the clearance of acute disease which will be relevant to future malaria-vaccine design and suggests the need for novel therapeutic solutions. This review will thus examine the role of PD-1-mediated T cell exhaustion in preventing lasting immunity against malaria.
    Frontiers in Microbiology 05/2014; 5:249. DOI:10.3389/fmicb.2014.00249 · 3.99 Impact Factor
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    • "The participation of CD8+ T cells and nitric oxide in the blood stages of malaria infection has been a matter of controversy 46. In this work, we provide evidence that splenic CD8+ cells undergo apoptosis at increased frequency and upregulate the expression of TNF-α mRNA on day 4 and IFN-γ and IL-10 mRNA on day 11 post-infection. "
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    ABSTRACT: Nitric oxide (NO) is involved in the clearance of several types of bacteria, viruses and parasites. Although the roles of NO and CD8+ T cells in the immune response to malaria have been extensively studied, their actual contributions during the blood stages of malaria infection remain unclear. In this work, we corroborate that serum NO levels are not associated with the in vivo elimination of the blood stages of Plasmodium chabaudi AS. In addition, we show that CD8+ T cells exhibit increased apoptosis and up regulate the expression of TNF-α mRNA on day 4 post-infection and IFN-γ and IL-10 mRNA on day 11 post-infection. Interestingly, only the levels of IFN-γ and IL-10 expression are affected when iNOS is inhibited with aminoguanidine (AG), suggesting that NO could be involved in the activation of CD8+ T cells during the blood stages of plasmodium infection.
    International journal of biological sciences 11/2011; 7(9):1401-11. · 4.51 Impact Factor
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    ABSTRACT: Pregnancy-associated malaria, a manifestation of severe malaria, is the cause of up to 200,000 infant deaths a year, through the effects of placental insufficiency leading to growth restriction and preterm delivery. Development of a vaccine is one strategy for control. Plasmodium falciparum-infected red blood cells accumulate in the placenta through specific binding of pregnancy-associated parasite variants that express the VAR2CSA antigen to chondroitin sulphate A on the surface of syncytiotrophoblast cells. Parasite accumulation, accompanied by an inflammatory infiltrate, disrupts the cytokine balance of pregnancy with the potential to cause placental damage and compromise foetal growth. Multigravid women develop immunity towards VAR2CSA-expressing parasites in a gravidity-dependent manner which prevents unfavourable pregnancy outcomes. Although current vaccine design, targeting VAR2CSA antigens, has succeeded in inducing antibodies artificially, this candidate may not provide protection during the first trimester and may only protect those women living in areas endemic for malaria. It is concluded that while insufficient information about placental-parasite interactions is presently available to produce an effective vaccine, incremental progress is being made towards achieving this goal.
    01/2011; 2011(1, supplement):764845. DOI:10.4061/2011/764845
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