Severe Malaria Infections Impair Germinal Center Responses by Inhibiting T Follicular Helper Cell Differentiation
Severe Malaria Infections Impair Germinal Center Responses by Inhibiting T Follicular Helper Cell Differentiation
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DOI：
10.1016/j.celrep.2015.12.006
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发表时间：
2016-01-05
期刊：
影响因子：
8.8
通讯作者：
Hansen, Diana Silvia
中科院分区：
文献类型：
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作者：
Ryg-Cornejo, Victoria;Ioannidis, Lisa Julia;Hansen, Diana Silvia
对疟疾的自然获得性免疫只有在多年反复接触疟原虫寄生虫后才能发展。尽管抗体在保护中起着关键作用，但缓慢获得免疫力的细胞过程仍然未知。使用小鼠模型，我们表明，严重的疟疾感染抑制在脾脏中的生殖中心（GC）的建立。我们证明，感染诱导高频率的T滤泡辅助（Tfh）细胞前体，但在受损的Tfh细胞分化的结果。尽管Bcl-6和IL-21高表达，但感染期间诱导的前体Tfh细胞显示低水平的PD-1和CXCR 5，并共表达Th 1相关分子，如T-bet和CXCR 3。阻断炎性细胞因子TNF和IFN-γ或T-bet缺失恢复了Tfh细胞分化和对感染的GC反应。因此，这项研究表明，相同的促炎介质，驱动严重的疟疾病理学有不利影响的诱导保护性B细胞反应。
Naturally acquired immunity to malaria develops only after years of repeated exposure to Plasmodium parasites. Despite the key role antibodies play in protection, the cellular processes underlying the slow acquisition of immunity remain unknown. Using mouse models, we show that severe malaria infection inhibits the establishment of germinal centers (GCs) in the spleen. We demonstrate that infection induces high frequencies of T follicular helper (Tfh) cell precursors but results in impaired Tfh cell differentiation. Despite high expression of Bcl-6 and IL-21, precursor Tfh cells induced during infection displayed low levels of PD-1 and CXCR5 and co-expressed Th1-associated molecules such as T-bet and CXCR3. Blockade of the inflammatory cytokines TNF and IFN-gamma or T-bet deletion restored Tfh cell differentiation and GC responses to infection. Thus, this study demonstrates that the same pro-inflammatory mediators that drive severe malaria pathology have detrimental effects on the induction of protective B cell responses.