Genesis of Defective Effector Lymphocytes in the Helminth-Coinfected Host

 描述(申请人提供)：摘要：蠕虫感染发生在世界各地的人群中，并可能调节对无关病原体的免疫反应。该领域的一个重要考虑是伴随的蠕虫感染可能会降低疫苗的效力。蠕虫感染如何调节1型免疫尚不清楚。以前的研究表明，Th2主导的免疫反应对蠕虫产物、宿主微生物区系的变化以及对T细胞激活的直接免疫调节作用。目前尚不清楚蠕虫感染如何影响效应细胞的形成和功能。利用小鼠与多脑回混合感染和弓形虫免疫的生态学模型，我们发现蠕虫感染抑制了效应器CD8T细胞的分化。此外，在合并感染的小鼠中产生的效应性CTL表现出固有的功能缺陷，其标志是Tfb1m缺乏和SPRY2上调。CD8T细胞分化缺陷与CD8+DC介导的IL-12反应受到抑制有关，而STAT6缺乏可缓解这种抑制作用。然而，单独缺乏STAT6并不足以挽救有缺陷的效应器分化。相反，需要联合阻断IL-4和IL-10以恢复CD8T细胞分化。为了解释IL-4和IL-10的双重需求，我们提出了蠕虫感染诱导这两种细胞因子在天然和获得性免疫组织环境中抑制效应CD8T细胞活化、增殖和分化的多个点的假设。我们提出了三个具体的目标，以促进我们对蠕虫免疫调节效应淋巴细胞生成的机制的理解。在目标1中，我们将使用新开发的分析方法和一种新的卵泡外生成效应性CD8T细胞的范例来追踪哪些关键检查点受到蠕虫联合感染的影响。在目标2中，我们专注于定义CD8T效应细胞如何成为固有缺陷，特别是SPRY2和Tfb1m在信号改变和线粒体生物发生和代谢缺陷中的作用。最后，在目标3中，我们将询问T细胞中IL-4和IL-10信号与其他天然和获得性免疫细胞在介导蠕虫免疫调节中的内在作用。我们还将整合和验证我们的一般假设，即蠕虫合并感染对1型获得性免疫的强大免疫调节是基于IL-4和IL-10对不同先天成分的联合抑制作用。

 DESCRIPTION (provided by applicant): 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. How helminth infection modulates type 1 immunity is unclear. Previously studies have suggested a regulatory role for helminth products, changes in host microbiota and direct immunoregulation of T cell activation by the Th2 dominated immune response. 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 intrinsic functional defect, marked by a deficiency in Tfb1m and upregulation of Spry2. Defective CD8 T cell differentiation was associated with an inhibition of the CD8+ DC mediated IL-12 response, which was relieved by STAT6 deficiency. However, the absence of STAT6 alone was not sufficient to rescue defective effector differentiation. Instead, combined blockade of IL-4 and IL-10 was required for restoration of CD8 T cell differentiation. To explain the dual requirement for IL4 and IL- 10, we propose the hypothesis that helminth infection induces these two cytokines to inhibit multiple points in the innate and adaptive immune tissue environments where the activation, proliferation and differentiation of effector CD8 T cells occur. We propose three specific aims to advance our mechanistic understanding of helminth immunomodulation of effector lymphocyte generation. In Aim 1, we will use newly developed analytical methods and a novel paradigm for extrafollicular generation of effector CD8 T cells to track which critical checkpoints are affected by helminth coinfection. In Aim 2, we focus on defining how CD8 T effector cells become intrinsically defective, particularly focusing on the roles of Spry2 and Tfb1m in altered signaling and defective mitochondrial biogenesis andmetabolism. Finally, in Aim 3, we will interrogate the cell intrinsic role of IL4 and IL-10 signaling in T cells versus other innate and adaptive immune cells in mediating helminth immunoregulation. We will also integrate and validate our general hypothesis that robust immunomodulation of type 1 adaptive immunity by helminth coinfection is based on the combined inhibitory effects of IL4 and IL-10 on distinct innate components.