A Major Role for Myeloid-Derived Suppressor Cells and a Minor Role for Regulatory T Cells in Immunosuppression during Staphylococcus aureus Infection

Abstract

Staphylococcus aureus can cause difficult-to-treat chronic infections. We recently reported that S. aureus chronic infection was associated with a profound inhibition of T cell responses. In this study, we investigated the mechanisms responsible for the suppression of T cell responses during chronic S. aureus infection. Using in vitro coculture systems, as well as in vivo adoptive transfer of CFSE-labeled OT-II cells, we demonstrated the presence of immunosuppressive mechanisms in splenocytes of S. aureus–infected mice that inhibited the response of OT-II cells to cognate antigenic stimulation. Immunosuppression was IL-10/TGF-β independent but required cell–cell proximity. Using DEREG and Foxp3gfp mice, we demonstrated that CD4+CD25+Foxp3+ regulatory T cells contributed, but only to a minor degree, to bystander immunosuppression. Neither regulatory B cells nor tolerogenic dendritic cells contributed to immunosuppression. Instead, we found a significant expansion of granulocytic (CD11b+Ly6G+Ly6Clow) and monocytic (CD11b+Ly6G−Ly6Chigh) myeloid-derived suppressor cells (MDSC) in chronically infected mice, which exerted a strong immunosuppressive effect on T cell responses. Splenocytes of S. aureus–infected mice lost most of their suppressive activity after the in vivo depletion of MDSC by treatment with gemcitabine. Furthermore, a robust negative correlation was observed between the degree of T cell inhibition and the number of MDSC. An increase in the numbers of MDSC in S. aureus–infected mice by adoptive transfer caused a significant exacerbation of infection. In summary, our results indicate that expansion of MDSC and, to a minor degree, of regulatory T cells in S. aureus–infected mice may create an immunosuppressive environment that sustains chronic infection.

IL-10 Plays Opposing Roles during Staphylococcus aureus Systemic and Localized Infections

“…In this study, we provide significant new insights into the role of IL-10 during both localized and systemic acute S. aureus infection. To date, S. aureus has primarily been shown to manipulate host production of IL-10 for its own advantage to facilitate survival during both chronic systemic and biofilm models of infection (21,23). Our study demonstrates divergent roles for IL-10 depending on the site of infection.…”

“…Adoptive transfer of MDSCs exacerbated systemic infection in recipient mice following S. aureus i.v. challenge (21). Similarly, during a chronic S. aureus orthopedic biofilm infection, Heim et al (22,23) observed an expansion of IL-10-producing MDSCs at the site of infection, which was associated with bacterial persistence.…”

“…Although both IL-10 and TGF-b were produced, immunosuppression was primarily dependent on cell-cell contact that inhibited effector T cell responses (21). Adoptive transfer of MDSCs exacerbated systemic infection in recipient mice following S. aureus i.v.…”

“…In a systemic model of chronic S. aureus bloodstream infection, kidney abscesses were still apparent on day 56 postinfection due to impaired T cell responses (20); subsequently, this immunosuppression was attributed to the expansion of myeloid-derived suppressor cells (MDSCs) and to a lesser extent Tregs in the spleens of infected mice compared with uninfected controls (21). Although both IL-10 and TGF-b were produced, immunosuppression was primarily dependent on cell-cell contact that inhibited effector T cell responses (21).…”

Propofol Sedation Exacerbates Kidney Pathology and Dissemination of Bacteria during Staphylococcus aureus Bloodstream Infections

“…Numerous recent studies have shown that MDSCs can play a pathological role during S. aureus infection. One study used splenocytes from S. aureus-infected mice cocultured in vitro with OT-II-specific T cells to show that S. aureus infection induced MDSCs that blocked T cell activation and proliferation in an antigen-specific, contact-dependent manner (72). Another study using an S. aureus skin infection model showed that cutaneous sensing of S. aureus through TLR2-6 pathways induced MDSC expansion, which negatively regulated T cell responses in the skin (73).…”