Induction of effector lymphocyte lethargy by helminth coinfection

摘要： 蠕虫感染发生在世界各地的人群中，并可能调节免疫 对无关病原体的反应。该领域的一个重要考虑是 伴随的蠕虫感染会降低疫苗的效力。目前尚不清楚 蠕虫感染如何影响效应细胞的形成和功能。使用 多脑回小鼠共感染的生态适宜模型及疫苗接种 对于弓形虫，我们发现蠕虫感染抑制了效应器CD8的分化 T细胞。此外，在合并感染的小鼠中产生的效应性CTL表现出 “嗜睡”表型，以Tfb1m缺乏和线粒体压低为特征 生物发生和缺陷效应细胞因子反应。CD8 T细胞分化缺陷 也与SPRY2的上调有关，SPRY2是一种负调控因子 受体信号。蠕虫混合感染诱导有缺陷的效应器分化 由宿主IL-4和IL-10介导。推进对蠕虫的机械性认识 诱导效应淋巴细胞的嗜睡，我们提出了三个具体的目标。在目标1中，我们将 利用我们最近开发的技术进步和洞察力来描述如何 蠕虫合并感染对CD8T细胞的激活、增殖和 差异化。在AIM2中，我们将询问线粒体不足的功能作用 蠕虫引起的效应器功能障碍。最后，在目标3中，我们将剖析SPRY2的作用 CD8T细胞固有的IL-4和IL-10信号在蠕虫诱导的淋巴细胞嗜睡中的作用。 总之，这些研究将促进对效应细胞的机制理解。 并为治疗逆转提供了途径。 好了！

Abstract: Helminth infections occur in populations worldwide and potentially modulate the immune response to unrelated pathogens. An important consideration in the field is that concomitant helminth infection could decrease the efficacy of vaccines. It is not known how helminth infection impacts the formation and function of effector cells. Using an ecologically appropriate model of mouse coinfection with H. polygyrus and vaccination with T. gondii, we find that helminth infection inhibited the differentiation of effector CD8 T cells. Furthermore, the effector CTLs that develop in coinfected mice exhibit an “lethargic” phenotype, marked by a deficiency in Tfb1m and depressed mitochondrial biogenesis and defective effector cytokine response. Defective CD8 T cell differentiation was associated also associated with an upregulation of Spry2, a negative regulator of receptor signaling. Induction of defective effector differentiation by helminth coinfection was mediated by host IL-4 and IL-10. To advance mechanistic understanding of helminth induced effector lymphocyte lethargy, we propose three specific aims. In Aim 1, we will leverage our recently developed technical advances and insights to delineate how helminth coinfection negatively impacts CD8 T cell activation, proliferation and differentiation. In Aim2, we will interrogate the functional role of mitochondrial insufficiency in helminth-induced effector dysfunction. Finally, in Aim 3, we will dissect the role of Spry2 and CD8 T cell intrinsic IL4 and IL-10 signaling in helminth-induced lymphocyte lethargy. Together, these studies will advance mechanistic understanding of effector cell dysfunction and provide avenues for therapeutic reversal. !