Decline of FoxP3+ Regulatory CD4 T Cells in Peripheral Blood of Children Heavily Exposed to Malaria.
Decline of FoxP3+ Regulatory CD4 T Cells in Peripheral Blood of Children Heavily Exposed to Malaria.
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DOI：
10.1371/journal.ppat.1005041
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发表时间：
2015-07
期刊：
影响因子：
6.7
通讯作者：
Feeney ME
中科院分区：
文献类型：
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作者：
Boyle MJ;Jagannathan P;Farrington LA;Eccles-James I;Wamala S;McIntyre TI;Vance HM;Bowen K;Nankya F;Auma A;Nalubega M;Sikyomu E;Naluwu K;Rek J;Katureebe A;Bigira V;Kapisi J;Tappero J;Muhindo MK;Greenhouse B;Arinaitwe E;Dorsey G;Kamya MR;Feeney ME
FoxP 3+调节性CD 4 T细胞（TCR 4）有助于维持病原体特异性免疫和免疫介导的病理之间的微妙平衡。先前的研究表明，Treg在体内和体外均由恶性疟原虫诱导;然而，在急性和慢性感染期间影响Treg稳态的因素及其在疟疾免疫发病机制中的作用仍不清楚。我们评估了在乌干达疟疾高发区居住的特征明确的儿童队列中Tcirrhosis的频率和表型。我们发现，FoxP 3 + T淋巴细胞在外周血中的频率和绝对数量显着下降，随着先前疟疾发病率的增加。纵向测量证实，这种下降只发生在高度接触疟疾的儿童中。外周血中TbR的下降伴随着寄生虫抗原对TbR的体外诱导减少，以及先前曾强烈暴露于疟疾的儿童中TbR上TNFR 2表达减少。虽然Treg频率与预防疟疾无关，但在Treg频率较低的儿童中，一旦感染恶性疟原虫，症状性疟疾的风险有降低的趋势。这些数据表明，慢性疟疾暴露导致Treg稳态改变，这可能影响自然暴露人群中抗疟免疫力的发展。在疟疾流行地区，免疫力发展缓慢，不能提供实质性的保护，防止再次感染。相反，在反复接触之后，年龄较大的儿童和成人最终会对感染的大多数症状表现产生保护作用。这可能部分归因于恶性疟原虫寄生虫诱导的免疫调节机制，如FoxP 3+调节性T细胞（TCFs）。先前的人类研究表明，TcR是由体内和体外的疟疾寄生虫诱导的，但这些细胞在长期暴露于疟疾的儿童中的免疫作用仍不清楚。在这项研究中，我们评估了来自乌干达疟疾高传播地区的儿童中Tendritis的频率和特征。我们发现，这种调节性T细胞群体随着疟疾发作次数的增加而显著下降。这种损失与TNFR 2的表达减少有关，TNFR 2是一种与TGFAP稳定性有关的蛋白质。此外，来自高度接触疟疾的儿童的T细胞在寄生虫刺激后分化为T细胞的倾向降低。总之，我们的数据表明，疟疾的反复发作改变了Treg的稳态，这可能会影响儿童对疟疾的免疫力的发展。
FoxP3+ regulatory CD4 T cells (Tregs) help to maintain the delicate balance between pathogen-specific immunity and immune-mediated pathology. Prior studies suggest that Tregs are induced by P. falciparum both in vivo and in vitro; however, the factors influencing Treg homeostasis during acute and chronic infections, and their role in malaria immunopathogenesis, remain unclear. We assessed the frequency and phenotype of Tregs in well-characterized cohorts of children residing in a region of high malaria endemicity in Uganda. We found that both the frequency and absolute numbers of FoxP3+ Tregs in peripheral blood declined markedly with increasing prior malaria incidence. Longitudinal measurements confirmed that this decline occurred only among highly malaria-exposed children. The decline of Tregs from peripheral blood was accompanied by reduced in vitro induction of Tregs by parasite antigen and decreased expression of TNFR2 on Tregs among children who had intense prior exposure to malaria. While Treg frequencies were not associated with protection from malaria, there was a trend toward reduced risk of symptomatic malaria once infected with P. falciparum among children with lower Treg frequencies. These data demonstrate that chronic malaria exposure results in altered Treg homeostasis, which may impact the development of antimalarial immunity in naturally exposed populations. In malaria endemic regions, immunity is slow to develop and does not provide substantial protection against reinfection. Rather, following repeated exposure, older children and adults eventually develop protection from most symptomatic manifestations of the infection. This may be due in part to the induction of immunoregulatory mechanisms by the P. falciparum parasite, such as FoxP3+ regulatory T cells (Tregs). Prior human studies have shown that Tregs are induced by malaria parasites both in vivo and in vitro, but the role of these cells in immunity in children who are chronically exposed to malaria remains unclear. In this study, we assessed the frequency and features of Tregs among children from areas of high malaria transmission in Uganda. We found that this regulatory T cell population declined markedly with increasing malaria episodes. This loss was associated with decreased expression of TNFR2, which is a protein implicated in stability of Tregs. Additionally, T cells from highly malaria exposed children demonstrated a reduced propensity to differentiate into Tregs following parasite stimulation. Together our data suggest that repeated episodes of malaria alter Treg homeostasis, which may influence the development of immunity to malaria in children.