Antigen delivery to dendritic cells shapes human CD4+ and CD8+ T cell memory responses to Staphylococcus aureus

Abstract

Intracellular persistence of Staphylococcus aureus favors bacterial spread and chronic infections. Here, we provide evidence for the existence of human CD4+ and CD8+ T cell memory against staphylococcal antigens. Notably, the latter could provide a missing link in our understanding of immune control of intracellular S. aureus. The analyses showed that pulsing of monocyte-derived dendritic cells (MoDC) with native staphylococcal protein antigens induced release of Th2-associated cytokines and mediators linked to T regulatory cell development (G-CSF, IL-2 and IL-10) from both CD4+ and CD8+ T cells, thus revealing a state of tolerance predominantly arising from preformed memory T cells. Furthermore, G-CSF was identified as a suppressor of CD8+ T cell-derived IFNγ secretion, thus confirming a tolerogenic role of this cytokine in the regulation of T cell responses to S. aureus. Nevertheless, delivery of in vitro transcribed mRNA-encoded staphylococcal antigens triggered Th1-biased responses, e.g. IFNγ and TNF release from both naïve and memory T cells. Collectively, our data highlight the potential of mRNA-adjuvanted antigen presentation to enable inflammatory responses, thus overriding the existing Th2/Treg-biased memory T cell response to native S. aureus antigens.

Staphylococcus aureus Protein A Induces Human Regulatory T Cells Through Interaction With Antigen-Presenting Cells

“…Several others also proved that Th17mediated immunity is essential during Sa infection (16)(17)(18)(19). Furthermore, we and others demonstrated that a human memory T cell repertoire exists in healthy individuals (20)(21)(22), underlining the importance of previous exposure.…”

“…In earlier studies, we saw that SpA induces Treg-associated cytokines in vitro (20). This study aimed to investigate the potential of this B cell superantigen in the induction of human Tregs.…”

Clonal Vγ6 + Vδ4 + T cells promote IL-17–mediated immunity against Staphylococcus aureus skin infection

“…Additionally, IFNγ-producing CD4 + T cells (Th1 cells) were found to contribute to protection against S. aureus skin infections in patients with HIV disease as well as in S. aureus wound and bacteremia infections in mouse models (21)(22)(23). Another study found that the IFNγ produced by human CD8 + T cells contributed to antigeninduced immunity against S. aureus (24). We previously reported that IFNγ and TNF protected against a recurrent S. aureus skin infection in mice deficient in IL-1β (25).…”

Messing with the Sentinels—The Interaction of Staphylococcus aureus with Dendritic Cells

“…In fact, healthy donors and patients show a large pool of S. aureus -specific memory T cells that respond to S. aureus with the secretion of IFN-γ and/or IL-17 [ 21 , 22 ]. The existence of CD8+ T cell memory cells and their responses against staphylococcal antigens are important for minimizing inflammation and promoting T cell tolerance [ 20 ]. Moreover, long-term exposure of mice to S. aureus failed to produce IL-2 after an antigen-specific T cell response, suggesting that T cells undergo anergy during persistent infection [ 143 ].…”

“…It is well known that most B cells require help by T cells to generate high affinity antibodies, such that the observation of a broad S. aureus -specific antibody repertoire indicates the existence of numerous S. aureus -specific T cells. Several recent studies have provided evidence for robust CD4+ and CD8+ T cell memory of staphylococcal antigens in humans [ 20 , 21 , 22 ].…”