Role of NFAT signaling in immune responses and protection against CMV

NFAT 信号在免疫反应和 CMV 保护中的作用

• 批准号: 421448670
• 负责人: Professorin Dr. Friederike Berberich-Siebelt
• 金额: --
• 依托单位: Pathologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/421448670?language=en
• 关键词: Role; NFAT; signaling; immune; responses

Human cytomegalovirus (HCMV) control hinges on a balance with host immune responses. Hence, adoptive immunotherapy with CD8+ T cells is sufficient to provide relief against opportunistic HCMV infections, which might occur upon allogenic hematopoietic (stem) cell transplantation (allo-HCT). In these patients, HCMV causes disease directly via viral cytotoxicity, but also exacerbates immunological incompatibility between co-transferred donor T cells and host tissue, thus aggravating graft-versus-host disease (GvHD). We demonstrated that signaling by two members of the family nuclear factors of activated T-cells (NFATc1 and NFATc2) plays a partly redundant role not only in GvHD upon immunotherapy, but also in T-cell responses to mouse CMV (MCMV) infection. Building on our results, we will study NFAT signaling in NK- and T-cell responses to CMV infection and GvHD using in vivo models of allo-HCT in MCMV latently infected mice and in vitro models of HCMV infection and co-culture with human NK and T cells. We will gene-edit NFATC1 and/or NFATC2 in human NK or CD8+ T cells and measure their ability to limit HCMV replication in co-cultured cells. Thereby, we will define the relevance of NFAT in the antiviral activity of human NK and CD8+ T cells. In vivo activity will be tested in the MCMV model by using mice with NFAT-ablated NK or T cells. We will compare NFAT-deficient and control mice for the emergence of NK memory cells, the profile of genes elicited and their ability to control virus replication. Furthermore, we will study the effects of these cells in latently infected mice in models of haploidentical HCT and GvHD. Here, it is important to establish the memory status in which CMV-specific NFAT-deficient T or NK cells should be during cell infusion in order to ensure protection. Taken together, we will determine role and relevance of NFAT for controlling CMV infection in clinically relevant settings.

人类巨细胞病毒（HCMV）控制与宿主免疫反应保持平衡。因此，使用CD8+ T细胞的过继免疫疗法足以防止机会性HCMV感染，这可能会在同种异性造血（STEM）细胞移植（Allo-HCT）上发生。在这些患者中，HCMV直接通过病毒细胞毒性引起疾病，但也加剧了共转移的供体T细胞和宿主组织之间的免疫学不相容性，从而加剧了疗法抗移植抗宿主病（GVHD）。我们证明，激活T细胞（NFATC1和NFATC2）的两个家族核因子的信号传导不仅在免疫疗法后在GVHD中发挥了部分冗余作用，而且在T细胞对小鼠CMV（MCMV）感染的反应中也起着作用。在我们的结果的基础上，我们将使用Allo-HCT在MCMV中的体内模型进行NK和T细胞对CMV感染和GVHD的响应中的NFAT信号传导，并在MCMV中的体内模型和HCMV感染的体外模型以及与人NK的体外模型和T细胞。我们将在人NK或CD8+ T细胞中基因编辑NFATC1和/或NFATC2，并测量其限制共培养细胞中HCMV复制的能力。因此，我们将定义NFAT在人NK和CD8+ T细胞的抗病毒活性中的相关性。通过将小鼠与NFAT驱动的NK或T细胞使用小鼠，体内活性将在MCMV模型中进行测试。我们将比较NFAT缺陷和控制小鼠的NK记忆细胞的出现，引起的基因谱以及它们控制病毒复制的能力。此外，我们将研究这些细胞在单倍型HCT和GVHD模型中的潜在感染小鼠中的作用。在这里，重要的是要确定CMV特异性NFAT缺陷T或NK细胞在细胞输注过程中应进行的内存状态，以确保保护。综上所述，我们将确定NFAT在临床相关环境中控制CMV感染的作用和相关性。