Regulatory T cell contributions to mucosal antiviral immunity

Abstract

Regulatory T cells (Tregs) prevent autoimmunity and limit immunopathology using a variety of suppressive mechanisms, yet their roles during an immune response against pathogens remains unclear. Following intravaginal herpes simplex virus (HSV) type 2 infection, mice lacking Tregs fail to control viral replication within the infected tissue, pointing to a role for Tregs in facilitating productive immune responses. CD4 T cells are necessary for successful anti-HSV-2 immune responses in mice; as such we examined the role of Tregs in the generation of HSV-2-specific CD4 T cells. Using adoptive transfer of T cell receptor transgenic CD4 T cells into Treg-sufficient or Treg-depleted mice prior to HSV-2 infection, we found that Tregs are required for timely accumulation of HSV-2-specific CD4 T cells within the infected tissues. Further, Tregs are critical for appropriate trafficking of dendritic cells (DCs) from the vaginal mucosa to the dLN, which results in fully effective CD4 T cell priming, activation, and ultimately migration to the infected tissues. Finally, using CTLA-4 conditional knockout mice, we demonstrate that in the context of HSV-2 infection, Tregs require CTLA-4 to allow for proper trafficking of migratory DCs. Taken together, our data highlight the critical role of Tregs in proper potentiation of adaptive immune responses to microbial infection.