Open Access

Staphylococcus (S.) aureus is a pathobiont, colonizing 20% of healthy adults persistently, while the remainder is colonized transiently, resulting in a general colonization rate of approximately 37%. Beside symptom-free colonization, S. aureus is the cause of different diseases, including self-limiting food poisoning, skin and soft tissue infections, but also life-threatening pneumonia, endocarditis and sepsis. Additionally, numerous studies suggest an involvement of S. aureus in allergic diseases, in which S. aureus colonizes up to 90% of patients. The high abundance of S. aureus in healthy individuals and patients with allergic diseases is enabled by the broad spectrum of its virulence factors. Among them are the T cell superantigens (SAgs). SAgs act on the immune system in multiple ways. On the one hand, they are superantigenic, i.e. they directly crosslink receptors on antigen-presenting cells (APCs) and T cells. This causes their toxicity, which is due to excessive proliferation of immune cells and cytokine release that can culminate in toxic shock syndrome and death. On the other hand, there are indications, that SAgs are recognized by the adaptive immune system in a conventional way. Most adults have high affinity SAg-specific antibodies that can neutralize the toxins. These antibodies are produced by B cells, which need SAg-specific T cell help for differentiation, presumably provided in a conventional cognate interaction. High levels of SAg-specific IgE were detected in various allergic diseases and linked to the pathology, strongly suggesting an allergenic role of SAgs. However, specific T cells that recognize SAgs as conventional antigens have never been demonstrated and characterized. In this study, we investigated the recognition of SAgs as conventional antigens by human T cells. This was made possible through the generation of SAg toxoids, which lack superantigenicity but retain the ability to be taken up by APCs, processed and presented to specific T cells in a conventional manner. The lack of residual superantigenicity was validated by analyzing the potential of the toxoids to oligoclonally expand T cells of specific TCR Vβ families and by comparing the immune cell transcriptome after stimulation with wild-type (WT) SAgs, toxoids and conventional S. aureus antigens. We demonstrated, that of the four tested toxoids (inactivated (i) SEA, iSEB, iTSST and iTSSTw) two lack superantigenicity (iSEA and iSEB). Using iSEA and iSEB as recall antigens for the restimulation of human T cells ex vivo, we discovered a robust SAg-specific T cell memory response. In particular, we found that T cells from healthy, non-symptomatic individuals exhibited a Type 2-polarized cytokine profile when stimulated with iSEA or iSEB. In contrast, patients with chronic rhinosinusitis with nasal polyps (CRSwNP) did not exhibit SEA- or SEB-specific Th2 cells. Additionally, we studied the humoral response and observed increased anti-SAg-IgE levels in the healthy individuals, but not in CRSwNP patients. While Type 1 and Type 3 immune responses are associated with a protection against S. aureus, the polarization towards Type 2 responses have been discussed to be non-protective and an immune evasion mechanism, which facilitates colonization. Insights into the involvement of SAgs in the polarization of a specific immune memory and in allergic diseases should be taken into consideration when designing vaccines against S. aureus for individuals with or without allergic diseases. This is important, because the pre-existing immune response to S. aureus antigens might be boosted by vaccination, which would be unwanted in case of a non-protective response profile.