Data_Sheet_1_A Critical Blimp-1-Dependent IL-10 Regulatory Pathway in T Cells Protects From a Lethal Pro-inflammatory Cytokine Storm During Acute Experimental Trypanosoma brucei Infection.PDF

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 IFNγ, 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 a Trypanosome brucei infection. 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 via T. brucei-infected tsetse flies. Our results show that conditional T cell-specific ablation of the IL-10 regulating Prdm1 gene (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 that T. brucei activates 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.

在诸多传染性疾病中，免疫应答犹如一把双刃剑。尽管其是保护性免疫的必需组成，但感染诱导的炎症若无法得到适度调控，则会产生有害影响，引发机体附带损伤，甚至可能导致宿主死亡。在此背景下，强效抗炎细胞因子白细胞介素-10（IL-10）的作用便尤为关键，其可抑制锥虫病标志性的促炎免疫应答。对该感染的有效防控，不仅需要针对寄生虫可变表面糖蛋白（VSG）被膜抗原的特异性抗体发挥作用，还需依赖主要由干扰素-γ（IFN-γ）、肿瘤坏死因子（TNF）及一氧化氮（NO）介导的促炎免疫应答。但必须严格管控炎症反应，因为在布氏锥虫（Trypanosome brucei）感染后10天内，IL-10缺陷小鼠就会因失控的细胞因子风暴而死亡。目前，人们对IL-10的相关细胞来源，以及其在锥虫病中表达的相关分子机制仍知之甚少。本研究借助IL-10报告基因小鼠品系（Vert-X）证实，在急性感染阶段，自然杀伤细胞（NK细胞）、CD8阳性T细胞、CD4阳性T细胞以及B细胞和浆细胞，均可作为脾脏与肝脏中IL-10的潜在细胞来源。IL-10的表达峰值出现在促炎细胞因子产生峰值之后，而后者与寄生虫血症峰值的控制过程相伴发生。无论是常规实验针刺感染，还是通过布氏锥虫感染采采蝇实现的生理性感染，均得到了相似的实验结果。本研究结果显示，对IL-10调控基因Prdm1（编码Blimp-1转录因子）进行条件性T细胞特异性敲除，会引发失控的锥虫诱导促炎综合征，这与感染IL-10缺陷小鼠的表型一致。该结果表明，若以宿主存活为考量，包括NK细胞在内的非T细胞来源的IL-10，其生物学作用相对有限。另一被认为可调控IL-10的细胞因子白细胞介素-27（IL-27），在感染过程中并未对IL-10的产生产生影响。综合以上结果，本研究表明布氏锥虫可在T细胞中激活一条依赖Blimp-1的IL-10调控通路，该通路作为关键的抗炎调控变阻器，在寄生虫血症急性阶段对宿主存活至关重要。