Composition and efficacy of cytotoxic T-cell responses determine virus elimination and immunopathology after virus infections
Year: 2010
Type: dissertation
Abstract: This study addresses different aspects of antiviral CD8+ T cell-mediated immunopathology using two mouse models of human diseases. After pulmonary infection with respiratory syncytial virus (RSV), disease is mainly mediated by cytotoxic T cells (CTL). We used MHC congenic mice to address the question to what extent the MHC-determined CD8+ T cell response contributes to the different outcomes after RSV infection of BALB/c (H-2d) and C57BL/6 (H-2b) mice. The two investigated MHC alleles had no impact on virus elimination, but influenced weight loss and pulmonary inflammation. The overall magnitude of the virus-specific CTL response was similar. However, the H-2d restricted CTL response was less diverse and of lower avidity, thereby probably contributing to delayed elimination of stimulating APCs followed by prolonged CTL activation and cytokine-mediated immunopathology. The concept of CTL-mediated disease due to prolonged antigen stimulation is well illustrated in another disease called hemophagocytic lymphohistiocytosis (HLH). This disease is due to defects in cytotoxicity and can be modelled by LCMV infection of perforin-deficient mice. In this study, we analyzed two mouse models of partially impaired cytotoxicity. LCMV infection of pearl mice (a mouse model for Hermansky-Pudlak syndrome type II - HPSII) induced a transient HLH, which was related to a delayed virus control. In addition, pearl CTLs showed a proliferation defect indicating that defective APCs also contributed to the phenotype. Since the only human HPSII patient who developed lethal HLH also had a RAB27A mutation, we also analyzed pearl mice heterozygous for a Rab27a mutation. This did not aggravate the cytotoxicity defect or the disease phenotype, suggesting that in that patient, HPSII was sufficient for the disease. LCMV infection of beige and souris mice (mouse models for Chèdiak-Higashi syndrome with different mutations in the Lyst gene) was used to investigate the impact of viral, T cell and host genetic factors on the threshold of HLH induction. After LCMV infection, beige mice developed disease that did not fulfil all criteria of HLH. The phenotype was slightly aggravated by higher virus doses, but not by increasing the precursor frequency of antiviral CTLs. However, severe disease was observed when souris mice were infected. Both beige and souris mice showed a comparable defect in NK cell cytotoxicity and degranulation. In contrast, the defect in CTL cytotoxicity and degranulation was more pronounced in souris mice. These mice failed to eliminate the virus leading to prolonged CTL activation and development of the cytokine-mediated immunopathology of HLH. This study shows that genetically determined subtle differences in the efficacy of the antiviral T cell response and their impact on the kinetic of virus and APC elimination can determine the outcome of a viral infection.
Author: Birthe Jessen
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3200559386