Genesis of Defective Effector Lymphocytes in the Helminth-Coinfected Host

 描述（由申请人提供）：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因素是，伴随蠕虫感染可能会降低疫苗的效力。蠕虫感染如何调节1型免疫力尚不清楚。以前的研究表明，蠕虫产品的调节作用，宿主微生物群的变化和T细胞活化的Th 2主导的免疫应答的直接免疫调节。目前尚不清楚蠕虫感染如何影响效应细胞的形成和功能。采用生态学上合适的小鼠与H.多脑回和接种T.弓形虫感染后，我们发现寄生虫感染抑制了效应性CD 8 T细胞的分化。此外，在共感染小鼠中产生的效应CTL表现出内在的功能缺陷，以Tfb 1 m缺陷和Spry 2上调为标志。缺陷性CD 8 T细胞分化与CD 8 + DC介导的IL-12应答的抑制相关，其通过STAT 6缺陷而缓解。然而，单独缺乏STAT 6不足以挽救有缺陷的效应子分化。相反，需要IL-4和IL-10的联合阻断以恢复CD 8 T细胞分化。为了解释对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抑制先天性和适应性免疫组织环境中的多个点的假设，其中效应CD 8 T细胞的活化，增殖和分化发生。我们提出了三个具体的目标，以促进我们的机制理解蠕虫免疫调节效应淋巴细胞的产生。在目标1中，我们将使用新开发的分析方法和一种新的范式，用于效应CD 8 T细胞的滤泡外生成，以跟踪蠕虫共感染影响哪些关键检查点。在目标2中，我们着重于确定CD 8 T效应细胞是如何成为内在缺陷的，特别是关注Spry 2和Tfb 1 m在改变信号传导和缺陷线粒体生物发生和代谢中的作用。最后，在目标3中，我们将询问IL-4和IL-10信号传导在T细胞与其他先天性和适应性免疫细胞介导蠕虫免疫调节中的细胞内在作用。我们还将整合并验证我们的一般假设，即蠕虫共感染对1型适应性免疫的强大免疫调节是基于IL-4和IL-10对不同先天组分的联合抑制作用。

 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.