Nair, Savita:

The role of CD4+ helper T cells in immunity to acute friend retroviral infection

Duisburg, Essen (2009), 126 Bl.
Dissertation / Fach: Biologie
Medizinische Fakultät » Universitätsklinikum Essen » Institut für Virologie
Dittmer, Ulf (Doktorvater, Betreuerin)
Esche, Helmut (GutachterIn)
Duisburg, Essen, Univ., Diss., 2009
Abstract:
Retroviruses are highly pathogenic microbes and have accounted for significant mortality and morbidity worldwide. Cytotoxic T lymphocytes (CTLs) are efficient in keeping the viral replication under control during acute phase of infection but lose their protective function during later stages under the suppressive effect of Regulatory T cells. As a result of this, the virus manage to escape immune surveillance to cause persistent infections for life. In life-threatening infections such as Human Immunodeficiency virus (HIV) or Human T-cell leukemia virus (HTLV-1) immune escape becomes critical. Role of CTLs is well defined in various retroviral infection models but role of CD4+ T helper(h) cells in retroviral immunity is poorly understood. Hence, we aimed at characterising the function of CD4+ T cells during the initial phase of infections using the Friend retrovirus (FV) murine infection model. FV infection causes lethal leukemia in most strains of mice and the mouse model helps in studying the basic mechanisms of immunological control and escape in both acute and persistent retroviral infections. In vivo depletion of Th cells in acutely infected mice demonstrated that Th cells were not only vital in controlling viral spread and onset of erythroleukemia but also in the maintenance of the FV-specific CD8+ T cell pool and production of neutralising antibodies. Tetramer-II kinetic analysis of FV-specific Th cell responses showed that magnitude of protective immune responses in FV resistant mice was much higher than in susceptible mice owing to different MHC backgrounds. Adoptive transfer of FV-specific TCR transgenic CD4+ T cells indicated that peak activation of FV specific donor Th cells was observed at 1wpi (weeks post infection) and remained activated until 3 wpi. IFN-gamma production was also maximum at 1wpi and 2wpi which resulted in decreasing the viral loads. However, no significant production of IFN-gamma was observed at 3 wpi in spite of Th cells being activated. Depletion of regulatory T cells (Tregs) in DEREG mice at 3wpi resulted in enhancement of IFN-gamma production by CD4+ T cells and thereby could significantly reduce viral loads. Current study demonstrates that helper T cells were critical for recovery from acute Friend retroviral infections and that regulatory T cells can cause immunosuppression of helper T cell effector functions thereby contributing towards viral persistence.