Advanced investigations on the activation, expansion and function of regulatory T cells during acute Friend retrovirus infection of mice

Ross, Jean Alexander GND

In retroviral infections, different immunological mechanisms are involved in the development of chronic infection. While CD4+ T cells induce inflammation and T cell recruitment, CD8+ T cells mediate killing of infected host cells. In the Friend retrovirus (FV) model, regulatory T cells (Tregs) were found to induce CD8+ T cell dysfunction before viral clearance is achieved and thus contribute to viral chronicity. Although studied for decades, the exact suppressive mechanism of Tregs in the FV model remains elusive and an unavailable therapeutic target. Therefore, possibilities to control the expansion and activation of Tregs have become interesting therapeutic options. In previous studies was shown, that complement C3b-based opsonization of FV virions increased the infectivity on dendritic cells (DC). Infected DCs showed impaired maturation and induction of Tregs, thus enhancing the Treg-mediated suppression of CD8+ T cells. In the first part of this thesis, it was confirmed that C3b-based opsonization increases the infectivity of FV in DCs but also in macrophages in vivo. Interestingly, infected DCs, especially when the infection level was higher because of complement opsonization of the virus, induced the activation and proliferation of Tregs in vitro. Therefore, it was not surprising that Treg expansion was delayed in C3ko mice during FV infection. This confirmed some of our in vitro findings in in vivo experiments. Surprisingly, the delayed Treg responses in C3ko mice did not affect CD8+ T cell responses and viral loads. Overall, the effect of C3b-based opsonization of virions, their increased infectivity in DCs and macrophages and subsequent Treg activation were shown to play a minor role during FV infection and immunity. Additionally, DCs were infected with F-MuLV, incubated with naïve mouse serum (NMS) of wildtype (wt) and C3 knockout (C3ko) mice. Afterwards their ability to expand Tregs in vitro was investigated and revealed, that the expansion of Tregs was similar in both groups. Overall the increased infectivity of opsonized FV was found in DCs and macrophages in vivo, but the absence of C3b opsonization in C3ko mice did not beneficially alter the course of Infection. Treg activation and functionality are known to be dependent on IL-2 and NF-κB subunit c-Rel signaling. In an attempt to reduce the number of Tregs during the late phase of acute FV infection, it was possible to inhibit the expansion of Tregs by therapy with anti-IL-2 antibodies or by the c-Rel inhibiting drug pentoxyfillene (PTXF) in the spleen. Nevertheless, this did not change the functionality of CD8+ T cells nor the control of viral replication. Finally, the role of CD39 in the suppressive capacity of Tregs was investigated by infection of CD39 knockout (CD39ko) mice with FV. The examination of Tregs and CD8+ T cells revealed that Tregs and their activation remain unaffected by the absence of CD39. Interestingly, an increased proportion of CD8+ T cells expressed IFNγ and TNFα in the spleen. Additionally, the viral loads in the spleen dropped to zero in CD39ko mice. In contrast, the bone marrow remained unaffected. Summarized, indications for the importance of CD39 in Treg-mediated suppression were found in the spleen, exclusively. Since the suppression was identical to wt mice in the bone marrow, the role of CD39 in Treg-mediated suppression is limited.

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Ross, J.A., 2020. Advanced investigations on the activation, expansion and function of regulatory T cells during acute Friend retrovirus infection of mice. https://doi.org/10.17185/duepublico/71419
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