NK-, NKT- and CD8-Derived IFNγ Drives Myeloid Cell Activation and Erythrophagocytosis, Resulting in Trypanosomosis-Associated Acute Anemia

African trypanosomes are the causative agents of Human African Trypanosomosis (HAT/Sleeping Sickness) and Animal African Trypanosomosis (AAT/Nagana). A common hallmark of African trypanosome infections is inflammation. In murine trypanosomosis, the onset of inflammation occurs rapidly after infection and is manifested by an influx of myeloid cells in both liver and spleen, accompanied by a burst of serum pro-inflammatory cytokines. Within 48 hours after reaching peak parasitemia, acute anemia develops and the percentage of red blood cells drops by 50%. Using a newly developed in vivo erythrophagocytosis assay, we recently demonstrated that activated cells of the myeloid phagocytic system display enhanced erythrophagocytosis causing acute anemia. Here, we aimed to elucidate the mechanism and immune pathway behind this phenomenon in a murine model for trypanosomosis. Results indicate that IFNγ plays a crucial role in the recruitment and activation of erythrophagocytic myeloid cells, as mice lacking the IFNγ receptor were partially protected against trypanosomosis-associated inflammation and acute anemia. NK and NKT cells were the earliest source of IFNγ during T. b. brucei infection. Later in infection, CD8+ and to a lesser extent CD4+ T cells become the main IFNγ producers. Cell depletion and transfer experiments indicated that during infection the absence of NK, NKT and CD8+ T cells, but not CD4+ T cells, resulted in a reduced anemic phenotype similar to trypanosome infected IFNγR-/- mice. Collectively, this study shows that NK, NKT and CD8+ T cell-derived IFNγ is a critical mediator in trypanosomosis-associated pathology, driving enhanced erythrophagocytosis by myeloid phagocytic cells and the induction of acute inflammation-associated anemia.非洲锥虫（African trypanosomes）是人类非洲锥虫病（Human African Trypanosomosis, HAT/昏睡病）与非洲动物锥虫病（Animal African Trypanosomosis, AAT/那加那病）的致病原。非洲锥虫感染的典型特征为炎症反应。在鼠类锥虫感染模型中，炎症于感染后快速发作，表现为肝脏与脾脏内髓系细胞浸润，同时伴随血清促炎细胞因子爆发。在寄生虫血症峰值达到后的48小时内，会出现急性贫血，红细胞百分比下降50%。借助新开发的体内红细胞吞噬检测法（in vivo erythrophagocytosis assay），本团队近期证实髓系吞噬系统的活化细胞可增强红细胞吞噬作用，进而引发急性贫血。本研究旨在阐明鼠类锥虫病模型中该现象背后的机制与免疫通路。研究结果显示，干扰素γ（IFNγ）在红细胞吞噬性髓系细胞的招募与活化中发挥关键作用：干扰素γ受体缺陷小鼠可部分抵御锥虫病相关炎症与急性贫血。在布氏锥虫布氏亚种（T. b. brucei）感染过程中，自然杀伤（NK）细胞与自然杀伤T（NKT）细胞是IFNγ的最早来源；感染后期，CD8+ T细胞以及少量CD4+ T细胞成为IFNγ的主要产生细胞。细胞清除与过继转移实验表明，感染过程中缺失NK、NKT及CD8+ T细胞（而非CD4+ T细胞）时，贫血表型会减轻，与感染锥虫的IFNγ受体敲除小鼠表型相似。综上，本研究证实，NK、NKT及CD8+ T细胞来源的IFNγ是锥虫病相关病理的关键介导因子，可驱动髓系吞噬细胞增强红细胞吞噬作用，并诱导炎症相关性急性贫血。