Regulatory T cells exert differential functions during the early and late stages of the immune response to respiratory virus infection

Abstract Human metapneumovirus (HMPV) is the second leading cause of viral lower respiratory illness in children, and can be severe in premature infants, immunocompromised persons, and the elderly. Clearance of HMPV is predominantly mediated by cytotoxic CD8+ T lymphocytes (CTLs). HMPV and other respiratory viruses induce CTL impairment, where virus-specific CTLs are unable to function for an optimal antiviral immune response. We recently demonstrated that the inhibitory receptor Programmed Cell Death-1 (PD-1) mediates early functional impairment of the CTL response to HMPV, influenza, and other respiratory viruses early in infection. However, CTLs became impaired by day 10 post-infection in PD-1-deficient mice, indicating that other immunoregulatory cells or molecules may be acting during HMPV infection. CD4+ regulatory T cells (Tregs) are suppressive in cancer and some infections. We found that Tregs were increased in both number and percentage and activated during HMPV infection. Treg depletion throughout infection significantly increased CTL functionality and reduced peak virus titer. Early depletion of Tregs led to reduced recruitment of HMPV-specific CTLs to the lung, while depletion late after infection maintained the proportion of HMPV-specific CTLs and accelerated virus clearance. These data suggest that Tregs may perform distinct functions at different stages of lung infection. Tregs may be beneficial during the priming stage of the immune response, but are overall detrimental in the setting of HMPV infection and could be a target for therapeutics.