A Critical Blimp-1-Dependent IL-10 Regulatory Pathway in T Cells Protects From a Lethal Pro-inflammatory Cytokine Storm During Acute ExperimentalTrypanosoma bruceiInfection
A Critical Blimp-1-Dependent IL-10 Regulatory Pathway in T Cells Protects From a Lethal Pro-inflammatory Cytokine Storm During Acute ExperimentalTrypanosoma bruceiInfection
复制标题
DOI：
10.3389/fimmu.2020.01085
复制
发表时间：
2020-06-04
影响因子：
7.3
通讯作者：
Magez, Stefan
中科院分区：
文献类型：
--
作者：
De Trez, Carl;Stijlemans, Benoit;Magez, Stefan
在许多传染病中，免疫反应就像一把双刃剑。虽然保护性免疫是必需的，但感染引起的炎症如果得不到适当的控制，可能是有害的，会造成附带的身体损伤，并可能导致死亡。正是在这种情况下，需要有效的抗炎细胞因子白细胞介素-10（IL-10）来抑制标志锥虫病的促炎免疫应答。这种感染的有效控制不仅需要寄生虫的可变表面糖蛋白（VSG）外壳抗原特异性抗体的作用，而且还需要主要由IFN γ，TNF和NO介导的促炎免疫应答。然而，严格控制炎症是强制性的，因为IL-10缺陷型小鼠在布氏锥虫感染的10天内死于不受限制的细胞因子风暴。IL-10的相关细胞来源及其与锥虫病相关产生有关的相关分子机制知之甚少。使用IL-10报告小鼠品系（Vert-X），我们在此证明NK细胞、CD 8（+）T细胞和CD 4（+）T细胞以及B细胞和浆细胞构成急性感染期间脾和肝内IL-10的潜在细胞来源。IL-10波跟随峰值促炎细胞因子产生，其伴随峰值寄生虫血症的控制。在常规的实验性针头感染和通过T的生理感染后观察到类似的结果。感染布鲁氏菌的采采蝇。我们的研究结果表明，条件性T细胞特异性消融IL-10调节Prdm 1基因（编码Blimp-1转录因子），导致不受控制的锥虫诱导的促炎综合征，如在感染的IL-10缺陷小鼠中观察到的。该结果表明，当考虑宿主存活时，源自非T细胞（包括NK细胞）的IL-10的生物学作用是次要的。细胞因子IL-27也被认为是IL-10调节剂，在感染期间不影响IL-10的产生。总之，这些数据表明，T.布鲁氏菌激活T细胞中的Blimp-1依赖性IL-10调节途径，其充当关键的抗炎变阻器，在寄生虫血症的急性期期间对于宿主存活是必需的。
In many infectious diseases, the immune response operates as a double-edged sword. While required for protective immunity, infection-induced inflammation can be detrimental if it is not properly controlled, causing collateral body damage and potentially leading to death. It is in this context that the potent anti-inflammatory cytokine interleukin-10 (IL-10) is required to dampen the pro-inflammatory immune response that hallmarks trypanosomosis. Effective control of this infection requires not just the action of antibodies specific for the parasite's variable surface glycoprotein (VSG) coat antigens, but also a pro-inflammatory immune response mediated mainly by IFN gamma, TNF, and NO. However, strict control of inflammation is mandatory, as IL-10-deficient mice succumb from an unrestrained cytokine storm within 10 days of aTrypanosome bruceiinfection. The relevant cellular source of IL-10 and the associated molecular mechanisms implicated in its trypanosomosis associated production are poorly understood. Using an IL-10 reporter mouse strain (Vert-X), we demonstrate here that NK cells, CD8(+)T cells and CD4(+)T cells as well as B cells and plasma cells constitute potential cellular sources of IL-10 within the spleen and liver during acute infection. The IL-10 wave follows peak pro-inflammatory cytokine production, which accompanied the control of peak parasitemia. Similar results were observed following conventional experimental needle infection and physiological infections viaT. brucei-infected tsetse flies. Our results show that conditional T cell-specific ablation of the IL-10 regulatingPrdm1gene (encoding for the Blimp-1 transcription factor), leads to an uncontrolled trypanosome-induced pro-inflammatory syndrome like the one observed in infected IL-10-deficient mice. This result indicates that the biological role of IL-10-derived from non-T cells, including NK cells, is of minor importance when considering host survival. The cytokine IL-27 that is also considered to be an IL-10 regulator, did not affect IL-10 production during infection. Together, these data suggest thatT. bruceiactivates a Blimp-1-dependent IL-10 regulatory pathway in T cells that acts as a critical anti-inflammatory rheostat, mandatory for host survival during the acute phase of parasitemia.