Mechanisms of regulatory T cell activation and expansion utilizing virus-specific CD8+ T cells (VIR10P.1172)

Abstract

Abstract The CD8+ T cell response to acute Friend virus (FV) infection is critical for recovery from lethal disease. However, in the late acute phase of infection this response becomes suppressed by regulatory T cells (Tregs), thereby leading to chronic infection. A major question regarding these events is how does FV infection induce the Treg response. We discovered a novel subset of natural Tregs that expand disproportionately in response to FV infection. These Tregs bear Vβ5+ T cell receptors, which are unique because of their known specificity for a superantigen (Sag) encoded by an endogenous retrovirus. Our results demonstrate that these Sag-reactive Tregs are independent of IL-2 but dependent on TNFα. Studies revealed that the expansion of these Tregs is actually driven the CD8+ T cell response. Activated, FV-specific CD8+ T cells upregulate membrane bound TNFα, which induces Vβ5+ Treg expansion by binding to TNFR2 receptors on the Tregs. Thus the expansion of the Vβ5+ Tregs is dependent on activated CD8+ T cells, the eventual targets of Treg-mediated suppression. These results demonstrate a new pathway of Treg expansion and two-way intercellular communication between Tregs and activated CD8+ T cells. Control by Tregs appears to be a natural mechanism to prevent immunopathological damage from CD8+ T cell responses that are too vigorous or too sustained. Modulation of this Treg subset has implications not only for the treatment of viral infections but also autoimmune diseases.