Abstract
Despite continuous exposure and development of specific immunity, Staphylococcus aureus (Sa) remains one of the leading causes of severe infections worldwide. Although innate immune defense mechanisms are well understood, the role of the T cell response has not been fully elucidated. Here, we demonstrate that Sa and one of its major virulence factors protein A (SpA) induce human regulatory T cells (Tregs), key players in immune tolerance. In human PBMC and MoDC/T cell cocultures CD4+CD25+CD127dim Tregs were induced upon stimulation with Sa and to a lower extent with SpA alone. Treg induction was strongly, but not exclusively, dependent on SpA, and independent of antigen presentation or T cell epitope recognition. Lastly, soluble factors in the supernatant of SpA-stimulated MoDC were sufficient to trigger Treg formation, while supernatants of MoDC/T cell cocultures containing Sa-triggered Tregs displayed T cell suppressive activity. In summary, our findings identify a new immunosuppressory function of SpA, which leads to release of soluble, Treg-inducing factors and might be relevant to establish colonization.
Highlights
The human commensal Staphylococcus aureus (Sa) is a major pathogen and leading cause of nosocomial infections, resulting in tens of thousands of deaths worldwide and causing billions of dollar economical damage per year [1,2,3]
Research focused on the humoral immune response against Sa since antibodies against this bacterium can be found in asymptomatically colonized individuals as well as in patients [9, 10]
Due to high infestation rates and frequent exposure, the human immune system mounts an immune response but repeatedly fails to prevent Sa infection. This highlights the superb capacity of Sa to trigger immunoregulatory processes that suppress proinflammatory immune responses required for clearance of Sa [20]
Summary
The human commensal Staphylococcus aureus (Sa) is a major pathogen and leading cause of nosocomial infections, resulting in tens of thousands of deaths worldwide and causing billions of dollar economical damage per year [1,2,3]. About 30% of the human population are colonized [4]. The increasing antibiotic resistance of Sa strains [so called MRSA, [5]], resulting in long-lasting infections, illustrates the urgent need for a protective vaccine. One of the many reasons is the lack of essential pieces in understanding the complex human immune response against this pathogen. Research focused on the humoral immune response against Sa since antibodies against this bacterium can be found in asymptomatically colonized individuals as well as in patients [9, 10].
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