Innate lymphocyte responses in inflammatory diseases

Abstract

The immune system is a highly sophisticated system that has evolved to protect the host from external and internal threats. However, under some circumstances the immune response can get dysregulated and cause inflammatory diseases. In this thesis, I focus on three sets of disorders resulting from dysregulated immune responses: sepsis, toxic shock syndrome (TSS), and inflammatory bowel disease (IBD). They are highly heterogenous in their presentation and immune response profile and so far, there are no treatment options specifically targeting these conditions. The aim of this thesis is therefore to gain deeper insight into the immune mechanisms underlying these disorders. We have focused on two types of immune cells which are early responders in inflammation and share features of both the innate and adaptive immune system: group 3 innate lymphoid cells (ILC3) and mucosal-associated invariant T (MAIT) cells.

The aim of paper I was to explore the role of the receptor GPR183 on ILC3s in the development of lymphoid structures in the colon at steady state and in promoting cell migration and tissue reorganization during colonic inflammation. Using mouse models and human IBD samples, we found that GPR183 on ILC3s senses oxysterols and is essential for the formation of cryptopatches and innate lymphoid follicles. In inflamed colon of both mice and humans, the oxysterol production in the surrounding tissue increased, resulting in migration of ILC3s out of the lymphoid tissues and towards the top of the colonic folds where they promoted recruitment of other immune cells.

In paper II and III, we aimed to investigate the contribution of MAIT cells to the proinflammatory cytokine storm in TSS. In paper II, ex vivo stimulation experiments revealed that despite their low frequencies, MAIT cells were major producers of pro-inflammatory cytokines in streptococcal TSS (STSS). Superantigens produced by group A streptococci (GAS) bound to the b chain of the MAIT TCR, resulting in activation of a large fraction of the MAIT cell pool. MAIT cells were also found to be highly activated in patients with STSS. In paper III, we next explored the role of redox signaling in the strong MAIT cell response in TSS. We found that the MAIT cell cytokine response was inhibited by antioxidant treatment while other T cells were unaffected. Antioxidants reduced the total IL-18 production by PBMCs, and blocked IL-12 and IL-18-mediated MAIT cell activation.

In paper IV, we investigated the MAIT cell phenotype in early samples from sepsis patients in the emergency room to evaluate the potential of MAIT cells as prognostic or diagnostic markers. MAIT cells were activated and reduced in frequency early during the sepsis response. Expression of the activation marker CD69 on MAIT cells was associated with lymphopenia, organ dysfunction and increased mortality. To summarize, this thesis reveals important novel insights on the roles of ILC3s in colonic inflammation and MAIT cells in sepsis and TSS.