CD4+ Regulatory T Cells Exert Differential Functions during Early and Late Stages of the Immune Response to Respiratory Viruses

Abstract

Acute respiratory virus infection (ARI) induces CD8⁺ T cells with diminished cytokine production and functional impairment. The role of cellular mediators of immune impairment, specifically CD4⁺ regulatory T cells (Tregs), is incompletely understood in ARI. Tregs are known suppressors of effector T cell function, but whether they are detrimental or beneficial in ARI remains controversial. We show in this paper that Treg depletion leads to increased CD8⁺ T cell function and lower virus titer in mice infected with human metapneumovirus. We further demonstrate that Tregs play a temporal role in the immune response to human metapneumovirus and influenza: Treg depletion before infection pathologically reduces virus-specific CD8⁺ T cell numbers and delays virus clearance, whereas depletion 2 d postinoculation enhances CD8⁺ T cell functionality without reducing virus-specific CD8⁺ T cell numbers. Mechanistically, Treg depletion during immune priming led to impaired dendritic cell and CD8⁺ T cell migration. Further, early Treg depletion was associated with immune skewing toward a type 2 phenotype characterized by increased type 2 innate lymphoid cells and T_H2 CD4⁺ T cells, which was not observed when Treg depletion was delayed until after inoculation. These results indicate that the presence of Tregs at inoculation is critical for efficient priming of the CD8⁺ T cell response to ARI, whereas later in infection, Tregs are dispensable for virus clearance.