Regulatory T cells in retroviral infections

Abstract

Tight regulation of immune responses is not only critical for preventing autoimmune diseases but also for preventing immunopathological damage during infections in which overactive immune responses may be more harmful for the host than the pathogen itself. Regulatory T cells (Tregs) play a critical role in this regulation, which was discovered using the Friend retrovirus (FV) mouse model. Subsequent FV studies revealed basic biological information about Tregs, including their suppressive activity on effector cells as well as the molecular mechanisms of virus-induced Treg expansion. Treg suppression not only limits immunopathology but also prevents complete elimination of pathogens contributing to chronic infections. Therefore, Tregs play a complex role in the pathogenesis of persistent retroviral infections. New therapeutic concepts to reactivate effector T-cell responses in chronic viral infections by manipulating Tregs also came from work with the FV model. This knowledge initiated many studies to characterize the role of Tregs in HIV pathogenesis in humans, where a complex picture is emerging. On one hand, Tregs suppress HIV-specific effector T-cell responses and are themselves targets of infection, but on the other hand, Tregs suppress HIV-induced immune hyperactivation and thus slow the infection of conventional CD4+ T cells and limit immunopathology. In this review, the basic findings from the FV mouse model are put into perspective with clinical and basic research from HIV studies. In addition, the few Treg studies performed in the simian immunodeficiency virus (SIV) monkey model will also be discussed. The review provides a comprehensive picture of the diverse role of Tregs in different retroviral infections and possible therapeutic approaches to treat retroviral chronicity and pathogenesis by manipulating Treg responses.

Fig 1. IL-2-dependent expansion of Tregs during FV infection.

Depicted in brown are Treg activation events dependent on FV infection. No direct interactions between viral antigens and Tregs are required. Depicted in gray are required homeostatic signaling events for FV-induced Treg expansion. Homeostatic signaling levels are sufficient although FV infections may up-regulate expression of some membrane receptors. APC, antigen-presenting cell; FV, Friend virus; GITR, glucocorticoid-induced TNF receptor-related protein; GITRL, GITR ligand; IL-2, interleukin 2; TCR, T-cell receptor; TNFα, tumor necrosis factor α; Treg, regulatory T cell.

Fig 2. IL-2-independent expansion of Tregs during FV infection.

Depicted in brown are Treg activation events dependent on FV infection. No direct interactions between exogenous viral antigens and Tregs are required. Depicted in gray are required homeostatic signaling events for FV-induced Treg expansion. FV infection indirectly up-regulates expression of TNFR2. FV, Friend virus; IL-2, interleukin 2; mb, membrane bound; Sag, superantigen; TNFR2, tumor necrosis factor receptor 2; Treg, regulatory T cell; Vβ5, T-cell receptor variable β chain 5.

Fig 3. Duality of Treg effects in retroviral infections.

Deterimental effects are depicted in brown, and beneficial effects are depicted in gray. Arrows indicate effects, while blocked lines indicate blocked activities. FV, Friend virus; LP-BM5, murine retrovirus LP-BM5; SIV, simian immunodeficiency virus; Treg, regulatory T cell.