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Role of Lymphotoxin Beta and Cell Adhesion Molecule (CEACAM1) in Innate and Adaptive Immune Activation

Khairnar, Vishal Shivajirao

The induction of the adaptive and innate immune system is essential for controlling viral infections. Balance between the innate immune system and adaptive immune responses results in better antiviral immune activation. Not enough or too much activation can lead to impairment of immune responses. In this thesis, we have investigated the role of enforced viral replication and different mechanisms by which adequate innate and adaptive immune responses are generated. Recently, it was shown that Usp18 dependent viral replication in splenic CD169+ macrophages are important to induce a sufficient type I interferon response resulting in the subsequent activation of adaptive immune responses. Here, in one study, we have shown that the intracellular replication of viral particles is sufficient to generate virus specific CD8 T cell responses. On the other hand, extracellular distribution of viral particles along the splenic conduits was necessary for inducing systemic levels of type I interferon (IFN-I). We have shown that Usp18 is important for viral replication, but that B cell-derived lymphotoxin beta is necessary for the extracellular distribution of virus along the marginal zone in spleen. In a further study, we have demonstrated a role of CEACAM1 in B cell survival, proliferation and innate immune activation. B cells are important part of immune system because they are in close proximity of blood-borne antigen in splenic circulation, they secrete antibodies and maintain the lymphoid architecture. We have shown that cell intrinsic signalling of CEACAM1 is essential for survival of proliferating B cells. CEACAM1 is involved in B-cell receptor and signals through the Btk/Syk/NF-κB axis. Absence of CEACAM1 signalling leads to reduced number of B-cells in lymphoid organs especially marginal zone B cells and CD169+ macrophages. Absence of CEACAM1 leads to poor anti-viral antibody secretion after systemic infection with cytopathic virus resulting in early death of Ceacam1–/– mice. In another set of experiment, we investigated the role of virus specific antibodies on adaptive immune activation. With the use of chronic virus strain LCMV-Docile, we determined whether enforced viral replication could occur in presence of virus-specific antibodies or virus-specific CD8 T cells. We found that after systemic recall infection, virus-specific antibodies allow viral replication in splenic marginal zone but controlled in peripheral organs resulting in strong CD8 T cell priming whereas, virus-specific CD8 T cells blunted viral replication in spleen but failed to control the persistent chronic viral infection. In conclusion, using several mouse models of noncytopathic and cytopathic viral infection, we have elucidated the functional role of lymphotoxin beta, CEACAM1 and virus-specific antibodies in immune function particularly during enforced viral replication in the spleen.

Die Aktivierung des adaptiven und angeborenen Immunsystems ist essentiell für die Kontrolle viraler Infektionen. Ausgeglichene Antworten des angeborenen und adaptiven Immunsystems führen zu einer verbesserten antiviraler Immunantwort. Zu geringe oder zu hohe Aktivierung führt zu einer verschlechterten Immunantwort. In dieser Arbeit wurde die Rolle der ‘’enforced virus replication’’ und verschiedene Mechanismen untersucht, welche eine adäquate angeborene und adaptive Immunaktivierung garantieren.

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Khairnar, Vishal Shivajirao: Role of Lymphotoxin Beta and Cell Adhesion Molecule (CEACAM1) in Innate and Adaptive Immune Activation. 2017.

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