Role of CEACAM1 in antiviral immune responses

在全身感染后，先天性和适应性免疫系统抑制病毒向易感器官的传播，以防止快速死亡。最近，我们发现肝脏中的枯否细胞吸收大部分病毒接种物并抑制病毒复制以响应I型干扰素。相反，脾脏中的抗原呈递细胞促进病毒复制，从而提供有效的抗原以启动I型干扰素和抗病毒CD 8 + T细胞应答。鉴定新的分子和机制，1）影响边缘区的病毒复制，2）启动干扰素产生细胞的募集和激活，3）启动病毒特异性CD 8 + 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（CEACAM 1）是癌胚抗原家族的成员，参与细胞间的结合相互作用，影响与细胞增殖、分化和迁移相关的各种信号转导活动。CEACAM 1可以由免疫细胞表达，并且主要被描述为肠道中T细胞的调节剂。CEACAM 1信号传导是否影响病毒感染期间的免疫应答仍然主要未知。在已发表的工作中，我们确定CEACAM 1对于脾中B细胞的存活是必需的。在B细胞受体活化后，CEACAM 1表达导致Syk、ERK和NF κ B p65的磷酸化，随后诱导存活基因Pax 5、Bcl 2、Bcl 6和Xap。病毒特异性B细胞上缺乏CEACAM 1限制了它们的扩增，导致Ceacam 1缺陷小鼠在感染细胞病变性水泡性口炎病毒后的抗病毒免疫应答缺陷和死亡。使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CEACAM 1表达对于病毒特异性CD 8 + T细胞的扩增是必需的。此外，我们发现CEACAM 1在病毒感染后调节干扰素-α的产生。在这项提案中，我们将确定病毒特异性CD 8 + T细胞上的CEACAM 1如何影响其增殖，存活和功能。此外，我们将确定CEACAM 1如何影响病毒感染期间抗原呈递细胞和干扰素产生细胞的先天免疫激活。CEACAM 1的二聚化将通过募集SHP 2抑制T细胞，单体CEACAM 1将通过募集c-Src激活T细胞的分子假设将得到证实。总之，这些研究将揭示CEACAM 1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.