Bacterial Regulation of Peripheral Immunity : Mechanistic insights from lactobacilli and Staphylococcus aureus

Abstract

There is a constant cross-talk between our immune system and the colonizing microbiota. The gut resident bacteria produce a broad range of molecules with regulatory activities in both local and distal tissues. Staphylococcus (S.) aureus is a commensal bacterium with high pathogenic potential due to production of several potent virulence factors including staphylococcal enterotoxins (SEs). These SEs are known to induce overwhelming T cell responses, which can result in a serious condition known as toxic shock syndrome. In contrast, several species of bacteria from the genus Lactobacillus exhibit probiotic features and promote beneficial physiological and immunological effects in its host. The underlying mechanisms behind bacterial activation and regulation of peripheral lymphocytes remain elusive. In this thesis, we explored how secreted factors present in the cell free supernatants (CFS) of cultured S. aureus and lactobacilli mechanistically impact the activation of different types of T cells and NK cells. In paper I, we investigated the influence of S. aureus-CFS and SEA on regulatory T cells and found that despite de novo induction of FOXP3 expression, TREG cells also produced pro-inflammatory cytokines, which associated with CD161-expression. In paper II, we could show that S. aureus-CFS and SEA induce proliferation, cytotoxicity and cytokine production in conventional and unconventional T- and NK cells. Moreover, we also showed that the lactobacilli-CFS were able to dampen immune cell activation, which was partly linked to lactobacilli-derived lactate. In paper III, we continued to investigate the mechanism behind Lactobacillus-mediated dampening of induced lymphocyte responses and identified extracellular membrane vesicles to be one of the main components involved in Lactobacillus-mediated regulation of cytokine responses. Other observations made in paper II brought about several questions regarding the ability of SEs to activate unconventional T- and NK cells, which lacks certain receptors known to be required for SE-mediated activation of conventional T cells. In paper IV, we therefore investigated the mechanism behind SE-mediated activation of γδ T-, MAIT- and NK cells and found that SEs indirectly activated γδ T- and NK cells, which required the presence of conventional αβ T cells. In summary, this thesis presents novel insights into how soluble components from bacteria modulate immune cell responses and extends the general understanding of bacterial influence on peripheral immunity. At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Submitted. Paper 4: Manuscript.</p