Role of CEACAM1 in antiviral immune responses

在全身感染后，先天和获得性免疫系统会阻止病毒传播到易受感染的器官，以防止迅速死亡。最近，我们发现肝脏中的Kupffer细胞吸收了大部分病毒接种，并抑制了病毒复制，以应对I型干扰素。相反，脾中的抗原提呈细胞强制病毒复制，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。识别新的分子和机制，1)影响边缘区域的病毒复制，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。癌胚抗原细胞黏附分子1(CEACAM1)是癌胚抗原家族的一员，参与细胞间的相互作用，影响与细胞增殖、分化和迁移相关的各种信号转导活动。CEACAM1可由免疫细胞表达，主要被描述为肠道T细胞的调节因子。CEACAM1信号在病毒感染过程中是否影响免疫反应仍是个未知数。在已发表的工作中，我们发现CEACAM1对于B细胞在脾中的生存是必不可少的。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的表达。CEACAM1的缺失限制了病毒特异性B细胞的增殖，导致Ceacam1基因缺陷小鼠感染细胞病理性水泡性口炎病毒后的抗病毒免疫应答缺陷和死亡。利用淋巴细胞性脉络膜脑膜炎病毒(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，我们还发现CEACAM1调节病毒感染后干扰素-α的产生。在这项提案中，我们将确定病毒特异性CD8+T细胞上的CEACAM1如何影响它们的增殖、存活和功能。此外，我们还将确定CEACAM1在病毒感染期间如何影响抗原提呈细胞和干扰素产生细胞的先天免疫激活。CEACAM1的二聚化将通过SHP2的募集而抑制T细胞，而单体CEACAM1将通过c-Src的募集来激活T细胞的分子假说将得到证实。总之，拟议的研究将揭示CEACAM1在病毒感染过程中的新机制。

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.