The immune system must constantly monitor the gastrointestinal tract for the presence of pathogens while tolerating trillions of commensal microbiota. It is clear that intestinal microbiota actively modulate the immune system to maintain a mutually beneficial relation, but the mechanisms that maintain homeostasis are not fully understood. Recent advances have begun to shed light on the cellular and molecular factors involved, revealing that a range of microbiota derivatives can influence host immune functions by targeting various cell types, including intestinal epithelial cells, mononuclear phagocytes, innate lymphoid cells, and B and T lymphocytes. Here, we review these findings, highlighting open questions and important challenges to overcome in translating this knowledge into new therapies for intestinal and systemic immune disorders.

Elevated levels of interleukin-18 (IL-18) are found in many chronic inflammatory disorders, including inflammatory bowel disease (IBD), and polymorphisms in the IL18R1-IL18RAP locus are associated with IBD susceptibility. IL-18 is an IL-1 family cytokine that has been proposed to promote barrier function in the intestine, but the effects of IL-18 on intestinal CD4+ T cells are poorly understood. Here, we demonstrate that IL-18R1 expression is enhanced on both effector and regulatory CD4+ T cells in the intestinal lamina propria, with Th17 cells exhibiting particularly high levels. We further show that, during steady state, intestinal epithelial cells (IEC) constitutively secrete IL-18 that acts directly on IL-18R1-expressing CD4+ T cells to limit colonic Th17 cell differentiation, in part by antagonizing IL-1R1-signalling. In addition, although IL-18R1 is not required for colonic Foxp3+ Treg cell differentiation, we found that IL-18R1 signaling was critical for Foxp3+ Treg cell mediated control of intestinal inflammation, where it promoted expression of key Treg effector molecules. Thus, IL-18 is a key epithelial-derived cytokine that differentially regulates distinct subsets of intestinal CD4+ T cells during both homeostatic and inflammatory conditions, a finding with potential implications for treatment of chronic inflammatory disorders.

Polymorphisms in the intracellular pattern recognition receptor gene NLRP3 have been associated with susceptibility to Crohn’s disease, a type of inflammatory bowel disease (IBD). Following tissue damage or infection, NLRP3 triggers the formation of inflammasomes, containing NLRP3, ASC and caspase-1, which mediate secretion of IL-1β and IL-18. However, the precise role of NLRP3 inflammasomes in mucosal inflammation and barrier protection remains unclear. Here we show that upon infection with the attaching/effacing (A/E) intestinal pathogen Citrobacter rodentium, Nlrp3−/− and Asc−/− mice displayed increased bacterial colonization and dispersion, more severe weight loss and exacerbated intestinal inflammation. Analyses of irradiation bone marrow chimeras revealed that protection from disease was mediated through Nlrp3 activation in non-hematopoietic cells and was initiated very early after infection. Thus, early activation of Nlrp3 in intestinal epithelial cells limits pathogen colonization and prevents subsequent pathology, potentially providing a functional link between NLRP3 polymorphisms and susceptibility to IBD.

The innate recognition of fungal pathogens is a crucial first step in the induction of protective antifungal immunity. Complement is thought to be one key component in this process, facilitating fungal recognition and inducing early inflammation. However, the roles of the individual complement components have not been examined extensively. Here we have used mice lacking C3 to examine its role in immunity to opportunistic fungal pathogens and show that this complement component is essential for resistance to infections with Candida albicans and Candida glabrata. We demonstrate that the absence of C3 impairs fungal clearance but does not affect inflammatory responses. We also show that the presence of C3 contributes to mortality in mice challenged with very high doses of Saccharomyces cerevisiae, although these effects were found to be mouse strain dependent.