Foxp3+ regulatory T cells are abundant in the intestine where they prevent dysregulated inflammatory responses to self and environmental stimuli. It is now appreciated that Treg cells acquire tissue-specific adaptations that facilitate their survival and function1; however, key host factors controlling the Treg response in the intestine are poorly understood. IL-1 family member IL-33 is constitutively expressed in epithelial cells at barrier sites2 where it functions as an endogenous danger signal or alarmin following tissue damage3. Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease (IBD) patients4-7 suggesting a role for this cytokine in the pathogenesis of IBD. In the intestine, both protective and pathologic roles for IL-33 have been described in murine models of acute colitis8-11 but its contribution to chronic inflammation remains ill defined. Here we show that the IL-33 receptor ST2 is preferentially expressed on colonic Treg (cTreg) cells, where it promotes Treg function and adaptation to the inflammatory environment. IL-33 signaling into T cells stimulates Treg responses in several ways. Firstly, it enhances transforming growth factor-β1 (TGF-β1) mediated differentiation of Treg cells and secondly, it provides a necessary signal for Treg accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of IBD, restrained Treg responses through inhibition of IL-33 responsiveness. These results demonstrate a hitherto unrecognized link between an endogenous mediator of tissue damage and a major anti-inflammatory pathway, and suggest that the balance between IL-33 and IL-23 may be a key controller of intestinal immune responses.

The microbiota plays a fundamental role in the induction, education and function of the host immune system. In return, the host immune system has evolved multiple means by which to maintain its symbiotic relationship with the microbiota. The maintenance of this dialogue allows the induction of protective responses to pathogens and the utilization of regulatory pathways involved in the sustained tolerance to innocuous antigens. The ability of microbes to set the immunological tone of tissues, both locally and systemically, requires tonic sensing of microbes and complex feedback loops between innate and adaptive components of the immune system. In this review, we will highlight the dominant cellular mediators of these interactions and discuss emerging themes associated with our current understanding of the homeostatic immunological dialogue between the host and its microbiota.

The skin represents the primary interface between the host and the environment. This organ is also home to trillions of microorganisms that play an important role in tissue homeostasis and local immunity1–4. Skin microbial communities are highly diverse and can be remodelled over time or in response to environmental challenges5–7. How, in the context of this complexity, individual commensal microorganisms may differentially modulate skin immunity and the consequences of these responses for tissue physiology remains unclear. Here we show that defined commensals dominantly affect skin immunity and identify the cellular mediators involved in this specification. In particular, colonization with Staphylococcus epidermidis induces IL-17A+ CD8+ T cells that home to the epidermis, enhance innate barrier immunity and limit pathogen invasion. Commensal-specific T-cell responses result from the coordinated action of skin-resident dendritic cell subsets and are not associated with inflammation, revealing that tissue-resident cells are poised to sense and respond to alterations in microbial communities. This interaction may represent an evolutionary means by which the skin immune system uses fluctuating commensal signals to calibrate barrier immunity and provide heterologous protection against invasive pathogens. These findings reveal that the skin immune landscape is a highly dynamic environment that can be rapidly and specifically remodelled by encounters with defined commensals, findings that have profound implications for our understanding of tissue-specific immunity and pathologies.

The heterogeneous course, severity, and treatment responses among patients with atopic dermatitis (AD; eczema) highlight the complexity of this multifactorial disease. Prior studies have used traditional typing methods on cultivated isolates or sequenced a bacterial marker gene to study the skin microbial communities of AD patients. Shotgun metagenomic sequence analysis provides much greater resolution, elucidating multiple levels of microbial community assembly ranging from kingdom to species and strain-level diversification. Here, we analyze microbial temporal dynamics from a cohort of pediatric AD patients sampled throughout the disease course. Species-level investigation of AD flares showed greater Staphylococcus aureus-predominance in patients with more severe disease and S. epidermidis-predominance in patients with less severe disease. At the strain-level, metagenomic sequencing analyses demonstrated clonal S. aureus strains in more severe patients and heterogeneous S. epidermidis strain communities in all patients. To investigate strain-level biological effects of S. aureus, we topically colonized mice with strains isolated from AD patients and controls. This cutaneous colonization model demonstrated S. aureus strain-specific differences in eliciting skin inflammation and immune signatures characteristic of AD patients. Specifically, S. aureus isolates from AD patients with more severe flares induced epidermal thickening and expansion of cutaneous Th2 and Th17 cells. Integrating high-resolution sequencing, culturing, and animal models demonstrated how functional differences of staphylococcal strains may contribute to the complexity of AD disease.

Both microbial and host genetic factors contribute to the pathogenesis of autoimmune disease1–4. Accumulating evidence suggests that microbial species that potentiate chronic inflammation, as in inflammatory bowel disease (IBD), often also colonize healthy individuals. These microbes, including the Helicobacter species, have the propensity to induce pathogenic T cells and are collectively referred to as pathobionts4–6. However, an understanding of how such T cells are constrained in healthy individuals is lacking. Here we report that host tolerance to a potentially pathogenic bacterium, Helicobacter hepaticus (H. hepaticus), is mediated by induction of RORγt+Foxp3+ regulatory T cells (iTreg) that selectively restrain pro-inflammatory TH17 cells and whose function is dependent on the transcription factor c-Maf. Whereas H. hepaticus colonization of wild-type mice promoted differentiation of RORγt-expressing microbe-specific iTreg in the large intestine, in disease-susceptible IL-10-deficient animals there was instead expansion of colitogenic TH17 cells. Inactivation of c-Maf in the Treg compartment likewise impaired differentiation and function, including IL-10 production, of bacteria-specific iTreg, resulting in accumulation of H. hepaticus-specific inflammatory TH17 cells and spontaneous colitis. In contrast, RORγt inactivation in Treg only had a minor effect on bacterial-specific Treg-TH17 balance, and did not result in inflammation. Our results suggest that pathobiont-dependent IBD is driven by microbiota-reactive T cells that have escaped this c-Maf-dependent mechanism of iTreg-TH17 homeostasis.