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.

Author summary

Staphylococcus aureus is deemed one of the most important nosocomial pathogens but, to date, there are no safe and protective vaccines. In this study we investigate the nature of the preformed T cell response to S. aureus antigens in healthy donors. Our data reveal that CD4 ⁺ and—so far not described—CD8 ⁺ T cell memory responses against native staphylococcal antigens exist but are skewed towards minimizing inflammation and promoting tolerance. The T cell response to staphylococcal antigens is characterized by the secretion of typical Th2 cytokines such as IL-5 and IL-13 and mediators associated with formation of T regulatory cells. Most importantly, G-CSF suppresses IFNγ release from pre-existent memory T cells. However, our data reveal that the use of mRNA-encoded antigens to trigger S. aureus-specific T cell responses bears the potential to override the tolerogenic bias. It favors TNF- and IFNγ-releasing T cells and may, thus, represent an innovative tool in prophylactic and therapeutic vaccine development.