The dynamics of T cells during persistent Staphylococcus aureus infection: from antigen‐reactivity to in vivo anergy

Induction of polyclonal B cell activation is a phenomenon observed in many types of infection, but its immunological relevance is unclear. In this study we show that staphylococcal protein A induces T cell–independent human B cell proliferation by enabling uptake of TLR-stimulating nucleic acids via the VH3+ BCR. We further demonstrate that Staphylococcus aureus strains with high surface protein A expression concomitantly trigger activation of human plasmacytoid dendritic cells (pDC). Sensitivity to chloroquine, cathepsin B inhibition, and a G-rich inhibitory oligodeoxynucleotide supports the involvement of TLR9 in this context. We then identify pDC as essential cellular mediators of B cell proliferation and Ig production in response to surface protein A–bearing S. aureus. The in vivo relevancy of these findings is confirmed in a human PBMC Nod/scidPrkdc/γc−/− mouse model. Finally, we demonstrate that co-operation of pDC and B cells enhances B cell–derived IL-10 production, a cytokine associated with immunosuppression and induction of IgG4, an isotype frequently dominating the IgG response to S. aureus. IL-10 release is partially dependent on TLR2-active lipoproteins, a hallmark of the Staphylococcus species. Collectively, our data suggest that S. aureus exploits pDC and TLR to establish B cell–mediated immune tolerance.

Section: Discussionsupporting

confidence: 55%

Pathogen-Triggered Activation of Plasmacytoid Dendritic Cells Induces IL-10–Producing B Cells in Response to Staphylococcus aureus

Parčina

Miranda-García

Durlanik

et al. 2013

“…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).…”

mentioning

confidence: 99%

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

Leech

Lacey

Mulcahy

et al. 2017

Self Cite

IL-10 is a potent anti-inflammatory mediator that plays a crucial role in limiting host immunopathology during bacterial infections by controlling effector T cell activation. Staphylococcus aureus has previously been shown to manipulate the IL-10 response as a mechanism of immune evasion during chronic systemic and biofilm models of infection. In the present study, we demonstrate divergent roles for IL-10 depending on the site of infection. During acute systemic S. aureus infection, IL-10 plays an important protective role and is required to prevent bacterial dissemination and host morbidity by controlling effector T cells and the associated downstream hyperactivation of inflammatory phagocytes, which are capable of host tissue damage. CD19+CD11b+CD5+ B1a regulatory cells were shown to rapidly express IL-10 in a TLR2-dependent manner in response to S. aureus, and adoptive transfer of B1a cells was protective during acute systemic infection in IL-10–deficient hosts. In contrast, during localized s.c. infection, IL-10 production plays a detrimental role by facilitating bacterial persistence via the same mechanism of controlling proinflammatory T cell responses. Our findings demonstrate that induction of IL-10 has a major influence on disease outcome during acute S. aureus infection. Too much IL-10 at one end of the scale may suppress otherwise protective T cell responses, thus facilitating persistence of the bacteria, and at the other end, too little IL-10 may tend toward fatal host-mediated pathology through excessive activation of T cells and associated phagocyte-mediated damage.

“…The smallcolony variants can later revert to the full virulent wild-type phenotype, a feature that can explain the recurrence of certain S. aureus infections months or even years after their apparent elimination (12). Recently, we reported that T cells play a protective role during S. aureus infection, but they lose their ability to respond to bacterial Ags with the transition from acute infection to persistence, and they exhibit a dysfunctional state that may explain their failure to promote sterilizing immunity (13). The failure to sustain T cell responsiveness could represent a major driving force for the development of S. aureus chronic infection.…”

mentioning

confidence: 99%

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

Tebartz

Horst

Sparwasser

et al. 2015

Self Cite

138

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.