Role of CEACAM1 in antiviral immune responses

CEACAM1 在抗病毒免疫反应中的作用

• 批准号: 287900951
• 负责人: Professor Dr. Karl Sebastian Lang
• 金额: --
• 依托单位: Institut für Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/287900951?language=en
• 关键词: Role; CEACAM1; antiviral; immune; responses

After systemic infection the innate and adaptive immune systems inhibit the spread of the virus to susceptible organs to prevent rapid death. Recently we found that Kupffer cells in the liver take up most of the virus inoculum and suppress virus replication in response to type I interferon. In contrast, antigen presenting cells in the spleen enforce viral replication and thereby provide efficient antigen to initiate type I interferon and antiviral CD8+ T cell responses. Identifying new molecules and mechanisms which 1) influence viral replication in marginal zone, 2) initiate recruitment and activation of Interferon producing cells and 3) initiate activation of virus-specific CD8+ T cells is the major focus of our lab. Carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), a member of the carcinoembryonic antigen family, is engaged in intercellular binding interactions that affect various signal transduction activities associated with cell proliferation, differentiation, and migration. CEACAM1 can be expressed by immune cells and has mainly been described as a regulator of T cells in the gut. Whether CEACAM1 signaling influences the immune response during viral infection remains mainly unknown. In published work we identified that CEACAM1 is essential for survival of B cells in the spleen. After B cell receptor activation, CEACAM1 expression resulted in phosphorylation of Syk, ERK and NF kappaB p65, which was followed by induction of the survival genes Pax5, Bcl2, Bcl6 and Xiap. Lack of CEACAM1 on virus-specific B cells limited their expansion, resulted in defective anti-viral immune response and death of Ceacam1 deficient mice after infection with cytopathic vesicular stomatitis virus. Using lymphocytic choriomeningitis virus (LCMV) we found in unpublished preliminary work that CEACAM1 expression was essential for expansion of virus-specific CD8+ T cells. In addition we found that CEACAM1 regulates the production of Interferon-alpha after virus infection. In this proposal we will determine how CEACAM1 on virus-specific CD8+ T cells influences their proliferation, survival and function. In addition we will determine how CEACAM1 influences innate immune activation of antigen presenting cells and Interferon-producing cells during virus infection. The molecular hypothesize that dimerization of CEACAM1 will inhibit T cells via recruitment of SHP2 and that monomeric CEACAM1 will activate T cells via recruitment of c-Src will be proven. In conclusion, the proposed studies will uncover new mechanisms of CEACAM1 during virus infection.

在全身性感染后，先天和适应性免疫系统抑制病毒向易感器官的扩散，以防止迅速死亡。最近我们发现肝脏中的库普弗细胞在I型干扰素的作用下吸收了大部分的病毒接种物并抑制了病毒的复制。相反，脾脏中的抗原提呈细胞加强病毒复制，从而提供有效的抗原来启动I型干扰素和抗病毒CD8+ T细胞反应。确定1)影响病毒在边缘区复制的新分子和机制，2)启动干扰素产生细胞的招募和激活，3)启动病毒特异性CD8+ T细胞的激活是我们实验室的主要重点。癌胚抗原细胞粘附分子1 （CEACAM1）是癌胚抗原家族的一员，参与细胞间结合相互作用，影响与细胞增殖、分化和迁移相关的各种信号转导活动。CEACAM1可以通过免疫细胞表达，主要被描述为肠道T细胞的调节剂。在病毒感染过程中，CEACAM1信号是否影响免疫反应仍然是未知的。在已发表的工作中，我们发现CEACAM1对脾脏中B细胞的存活至关重要。在B细胞受体激活后，CEACAM1的表达导致Syk、ERK和NF kappaB p65的磷酸化，随后诱导生存基因Pax5、Bcl2、Bcl6和Xiap的磷酸化。病毒特异性B细胞缺乏CEACAM1限制了它们的扩增，导致CEACAM1缺陷小鼠感染细胞病变性水泡性口炎病毒后抗病毒免疫应答缺陷和死亡。利用淋巴细胞性脉络丛脑膜炎病毒（LCMV），我们在未发表的初步工作中发现CEACAM1的表达对于病毒特异性CD8+ T细胞的扩增是必不可少的。此外，我们发现CEACAM1在病毒感染后调节干扰素- α的产生。在这个提议中，我们将确定CEACAM1对病毒特异性CD8+ T细胞的影响，它们的增殖，存活和功能。此外，我们将确定CEACAM1如何影响病毒感染期间抗原提呈细胞和干扰素产生细胞的先天免疫激活。分子假设CEACAM1的二聚化将通过募集SHP2抑制T细胞，而单个CEACAM1将通过募集c-Src激活T细胞将被证明。总之，所提出的研究将揭示CEACAM1在病毒感染过程中的新机制。