Regulatory T cells (Tregs) are immunosuppressive cells of the immune system that control autoimmune reactivity. Tregs also respond during immune reactions to infectious agents in order to limit immunopathological damage from potent effectors such as CD8+ cytolytic T lymphocytes. We have used the Friend virus (FV) model of retroviral infection in mice to investigate how viral infections induce Tregs. During acute FV infection, there is significant activation and expansion of thymus-derived (natural) Tregs that suppress virus-specific CD8+ T cell responses. Unlike conventional T cells, the responding Tregs are not virus specific, so the mechanisms that induce their expansion are of great interest. We now show that B cells provide essential signals for Treg expansion during FV infection. Treg responses are greatly diminished in B cell-deficient mice but can be restored by adoptive transfers of B cells at the time of infection. The feeble Treg responses in B cell-deficient mice are associated with enhanced virus-specific CD8+ T cell responses and accelerated virus control during the first 2 weeks of infection. In vitro experiments demonstrated that B cells promote Treg activation and proliferation through a glucocorticoid-induced receptor superfamily member 18 (GITR) ligand-dependent mechanism. Thus, B cells play paradoxically opposing roles during FV infection. They provide proliferative signals to immunsosuppressive Tregs, which slows early virus control, and they also produce virus-specific antibodies, which are essential for long-term virus control.
The primary role of B cells in immunity is considered the production of pathogen-specific antibodies, but another, less-well-studied, function of B cells is to present foreign antigens to T cells to stimulate their activation and proliferation. Dendritic cells (DCs) are considered the most important antigen-presenting cells (APCs) for CD8+ T cells, but DCs lose APC function when infected with Friend virus (FV), a model retrovirus of mice. Interestingly, B cells were better able to stimulate CD8+ T cell responses when they were infected with FV. We also found that the activation status of B cells under homeostatic conditions was potently modulated by regulatory T cells. This study illustrates an important link between B cell and T cell responses and illustrates an additional mechanism by which regulatory T cells suppress critical T cell responses during viral infections.
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