Type I Interferons Negatively Regulate Foxp3+ Regulatory T Cells during Acute Viral Infection and Autoimmunity

Thesis (Ph.D.)--University of Washington, 2014CD4+ regulatory T (Treg) cells expressing the transcription factor Foxp3 are potent anti- inflammatory cells capable of restraining immune responses to both self- and foreign-antigens. In addition to preventing autoimmunity and immunopathology, Treg cells can also inhibit immune responses during viral, bacterial, and parasitic infections. Paradoxically, signals known to drive Treg proliferation, such as IL-2 and activated dendritic cells, are also abundant during infection when Treg activity may need to be curbed. How Treg activity is restrained during infection to allow for the generation of effective immune responses remains largely unclear. Type I interferons (IFNs) are a family of cytokines that coordinately regulate many cell types during viral infection, but their effects on Treg cells remain largely unknown. Here, we demonstrate that type I IFNs directly inhibit co-stimulation-dependent Treg proliferation and activation both in vitro and in vivo during acute infection with lymphocytic choriomeningitis virus (LCMV). This inhibition is cell-intrinsic and preferentially targets CD62LloCD44hi effector/memory Treg cells. Moreover, loss of the type I IFN receptor specifically in Treg cells results in functional impairment of virus-specific CD8+ and CD4+ T cells and inefficient viral clearance. Together, these data indicate that inhibition of Tregs by IFNs during acute viral infection is necessary for the development of robust anti-viral T cell responses. Because overexpression of type I interferons is associated with the development of many autoimmune disorders, we also asked how chronic IFN overexpression regulates Treg cell activity and how this contributes to immune dysfunction during IFN-associated autoimmune diseases. Using a well-established in vivo assay of Treg cell function, we show that Treg cell function is impaired in mice that chronically overproduce type I IFNs due to loss of the DNA exonuclease Trex1. Treg cell dysfunction completely depended on type I IFN signaling in T cells. Although IFN overexpression directly inhibited Treg cell proliferation and activation, this direct inhibition was not required for Treg cell dysfunction. Rather, chronic IFN expression directly promoted the expansion of conventional T cells, and inflammatory disease was completely dependent on IFNaR signaling in conventional T cells. Thus, chronic IFN expression drives inflammatory disease by impairing Treg cell function in vivo, both directly and indirectly through its effects on conventional T cells