Staphylococcus (S.) aureus is a common commensal and opportunistic pathogen that can produce several potent virulence factors, among which are the staphylococcal enterotoxins (SE). SE act as superantigens by crosslinking the T cell receptor (TCR) with the MHC-II on antigen presenting cells (APCs), subsequently leading to polyclonal T cell activation that can result in toxic shock syndrome. In this thesis, we have investigated different aspects of the response to SEA, one of the most produced SE by S. aureus. 

In paper I we focused on the activation of monocytes, and showed increased transcriptional responses related to inflammation, infection and dermatitis upon SEA stimulation. We demonstrated that posterior differentiation of these monocytes into monocyte-derived macrophages (MDMs) led to an altered phenotype, including reduced expression of antigen presentation and costimulatory molecules, but paradoxically increased induction of T cell proliferation and IFN-γ production. 

In paper II, we investigated how SE are able to activate MAIT cells, γδ T cells and NK cells, which lack the appropriate receptors to directly interact with SE. We demonstrated that their activation is secondary to that of APCs and conventional T cells. Upon SE encounter, APCs will produce high levels of IL-12, which induces the prompt activation and secretion of IL-2 and IFN-γ by conventional T cells. Cytokine signaling together with direct cell-to-cell contact with APCs and conventional T cells then lead to extensive IFN-γ production by MAIT, γδ T and NK cells.

Last, we investigated the effects of SEA across different immune landscapes, namely early life, pregnancy and allergy. In paper II, we observed an early life diminished immune response to SEA, characterized by delayed and lower cytokine secretion and impaired activation of γδ T cells and NK cells in cord blood and blood samples from 2-year-olds. In paper III we demonstrated that SEA stimulation leads to diminished IFN-γ and TNF responses in allergic individuals, most prominently in MAIT, γδ T and NK cells. However, these differences are overridden in the context of pregnancy. We also assessed APC markers, finding pregnancy-related and allergy-driven alterations in CD14, CD16, CD163, and HLA-DR expression, highlighting divergent immune regulation in these contexts.

Overall, we provide evidence for the crucial role of SEA in shaping immune function and regulation. We show that conventional T cells and APCs are essential in activating other lymphocytes, which subsequently contribute to the bulk of the excessive immune response caused by SEA. By examining the influence of different immune landscapes in the response to SEA, we not only enhance our understanding of superantigen biology but also expand our knowledge of factors that contribute to the immune responses in S. aureus-related diseases.