Role of CEACAM1 in antiviral immune responses

• Applicant: Professor Dr. Karl Sebastian Lang
• Subject Area: Immunology ; Virology
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 287900951

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 Using lymphocytic choriomeningitis virus (LCMV) we found in unpublished preliminary work that CEACAM1 expression was essential for expansion of virus-specific CD8+ T cells.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.

• DFG Programme: Research Grants