Characterization of myeloid-derived suppressor cells during acute Friend retrovirus infection of mice

Myeloide Suppressorzellen (MDSCs) wurden vor kurzem auf Grund ihrer Suppression von T-Zellen identifiziert. Der inhibitorische Einfluss von MDSCs wurde in verschiedenen Tumorerkrankungen beobachtet. Die Funktion dieser Zellen während der viralen Infektion ist jedoch bis heute nicht vollständig verstanden. Das Friend Virus Mausmodell eignet sich sowohl für die Untersuchung der akuten als auch der chronischen retroviralen Infektion. Ähnlich wie bei Infektionen mit dem Humanen Immundefizienz-Virus (HIV) oder Hepatitis-C-Virus (HCV), bekämpfen zytotoxische virus-spezifische CD8+ T-Lymphozyten (CTLs) die akute Virusinfektion, wohingegen sie während der chronischen Infektion dysfunktional sind. Insgesamt wurde in dieser Doktorarbeit der Einfluss von Myeloiden Suppressorzellen auf zytotoxische CD8+ T-Zellen während der akuten Friend Virus Infektion untersucht. Zwei Populationen von MDSCs, granulozytäre MDSCs (gMDSCs) und monocytäre MDSCs (mMDSCs) werden während der späten Phase der akuten FV Infektion expandiert, was mit einer CD8+ T-Zell-Kontraktion korreliert. Eine Population der MDSCs, die Granulozytären MDSCs, zeigen einen suppressiven Einfluss auf die CD8+ T-Zell-Proliferation und die Produktion von zytotoxischen Granula in vivo. Dieser Effekt kann durch verschiedene Mechanismen modelliert werden, wie beispielsweise PD-L1, Arginase, Stickstoffmonoxid oder CD39. Die Interaktion zwischen verschiedenen hemmenden Mechanismen, wie Myeloide Suppressorzellen, regulatorischen T-Zellen und inhibitorischen Rezeptoren und Liganden während der akuten FV Infektion wurde beobachtet. Die Elimination von zwei wichtigen immunregulatorischen Mechanismen führte nach Depletion der regulatorischen T-Zellen und der Blockierung von PD-L1 und TIM3 zur Expansion der Myeloiden Suppressorzellen und einer neuen, durch CD11bdim charakterisierten Population, die starke supprimierende Effekte gegenüber CD8+ T-Zellen zeigt. Myeloide Suppressorzellen spielen eine wichtige Rolle bei der Regulation der Immunantwort. Die in dieser Arbeit vorgestellten Ergebnisse, d. h. die hemmende Rolle von Myeloide Suppressorzellen während der akuten Friend Virus Infektion, können als Ansatz für eine Immuntherapie retroviraler Infektionen verwendet werden.A recently observed population of myeloid-derived suppressor cells (MDSCs) restrains the T cell immune response by showing robust suppressive activity. The inhibitory influence of MDSCs was observed in different tumor diseases. First attempts to describe MDSCs in infectious diseases were conducted. Nonetheless, the role of these cells during viral infection is not fully understood. Friend virus is a good model to study both acute and chronic retroviral infections. In the FV model, similar to the Human Immunodeficiency Virus (HIV) or Hepatitis C Virus (HCV) infections, cytotoxic virus-specific CD8+ T Lymphocytes (CTLs) efficiently control acute virus infections but become exhausted when a chronic infection develops. The data presented in this thesis evidences the influence of myeloid derived suppressor cells on cytotoxic CD8+ T cells during acute Friend Virus infection. Two populations of MDSCs, granulocytic MDSCs (gMDSCs) and monocytic MDSCs (mMDSCs), are expanding during the late phase of acute FV infection, which may be correlated with the CD8+ T cell contraction. Additionally, the in vivo elimination of the expanded population of granulocytic MDSCs shows the suppressive influence of these cells on CD8+ T cell proliferation and their production of cytotoxic granules. This effect may be mediated by several mechanisms, as proven in vitro, such as PD-L1, arginase, nitric oxide and CD39. Furthermore, possible compensatory interactions between different inhibitory mechanisms, such as myeloid derived suppressor cells, T regulatory cells, and inhibitory receptors/ligands were observed. Finally, the elimination of two important immune regulatory mechanisms after the depletion of T regulatory cells, and blocking of PD-L1 and Tim3 resulted in an expansion of myeloid derived suppressor cells with appearance of the new CD11bdim population of cells. The newly revealed population was showing strong suppressive activity against CD8+ T cells during acute retroviral infection. Myeloid derived suppressor cells play an important role in the regulation of the immune response. Thus, the results presented in this thesis show the inhibitory role of myeloid derived suppressor cells in the Friend virus infection and may be a possible target for the immune therapy of retroviral infections

Combination immunotherapy with anti-PD-L1 antibody and depletion of regulatory T cells during acute viral infections results in improved virus control but lethal immunopathology

Combination immunotherapy (CIT) is currently applied as a treatment for different cancers and is proposed as a cure strategy for chronic viral infections. Whether such therapies are efficient during an acute infection remains elusive. To address this, inhibitory receptors were blocked and regulatory T cells depleted in acutely Friend retrovirus-infected mice. CIT resulted in a dramatic expansion of cytotoxic CD4+ and CD8+ T cells and a subsequent reduction in viral loads. Despite limited viral replication, mice developed fatal immunopathology after CIT. The pathology was most severe in the gastrointestinal tract and was mediated by granzyme B producing CD4+ and CD8+ T cells. A similar post-CIT pathology during acute Influenza virus infection of mice was observed, which could be prevented by vaccination. Melanoma patients who developed immune-related adverse events under immune checkpoint CIT also presented with expanded granzyme-expressing CD4+ and CD8+ T cell populations. Our data suggest that acute infections may induce immunopathology in patients treated with CIT, and that effective measures for infection prevention should be applied

Combination immunotherapy with anti-PD-L1 antibody and depletion of regulatory T cells during acute viral infections results in improved virus control but lethal immunopathology

Combination immunotherapy (CIT) is currently applied as a treatment for different cancers and is proposed as a cure strategy for chronic viral infections. Whether such therapies are efficient during an acute infection remains elusive. To address this, inhibitory receptors were blocked and regulatory T cells depleted in acutely Friend retrovirus-infected mice. CIT resulted in a dramatic expansion of cytotoxic CD4+ and CD8+ T cells and a subsequent reduction in viral loads. Despite limited viral replication, mice developed fatal immunopathology after CIT. The pathology was most severe in the gastrointestinal tract and was mediated by granzyme B producing CD4+ and CD8+ T cells. A similar post-CIT pathology during acute Influenza virus infection of mice was observed, which could be prevented by vaccination. Melanoma patients who developed immune-related adverse events under immune checkpoint CIT also presented with expanded granzyme-expressing CD4+ and CD8+ T cell populations. Our data suggest that acute infections may induce immunopathology in patients treated with CIT, and that effective measures for infection prevention should be applied