We describe a reporter mouse strain designed to fate-map cells that have activated IL-17A. Here we show that TH17 cells show distinct plasticity in different inflammatory settings. Chronic inflammatory conditions in EAE caused a switch to alternative cytokines in TH17 cells, whereas acute cutaneous infection with Candida albicans, did not result in deviation of TH17 to alternative cytokine production, although IL-17A production was shut off in the course of the infection. During development of EAE, IFN-γ and other pro-inflammatory cytokines in the spinal cord were produced almost exclusively by ‘ex-TH17’ cells whose conversion was driven by IL-23. Thus, this model allows relating the actual functional fate of effector T cells to TH17 developmental origin irrespective of IL-17 expression.

Bacteriophage P1 Cre/loxP based systems can be used to manipulate the genomes of mice in vivo and in vitro, allowing the generation of tissue‐specific conditional mutants. Wehave generated mouse lines expressing Cre recombinase in hematopoietic tissues using the vav regulatory elements, or in lymphoid cells using the hCD2 promoter and locus control region (LCR). The R26R‐EYFP Cre reporter mouse line was used to determine the pattern of Cre expression in each line and enabled the assessment of Cre activity at a single‐cell level. Analysis showed that the vav promoter elements were able to direct Cre‐mediated recombination in all cells of the hematopoietic system. The hCD2 promoter and LCR on the other hand were able to drive Cre‐mediated recombination only in T cells and B cells, but not in other hematopoietic cell types. Furthermore, in the appropriate tissues, deletion of the floxed target was complete in all cells, thereby excluding the possibility of variegated expression of the Cre transgene. Both of these Cre‐transgenic lines will be useful in generating tissue‐specific gene deletions within all the cells of hematopoietic or lymphoid tissues.

The enteric nervous system (ENS) in mammals forms from neural crest cells during embryogenesis and early postnatal life. Nevertheless, multipotent progenitors of the ENS can be identified in the adult intestine using clonal cultures and in vivo transplantation assays. The identity of these neurogenic precursors in the adult gut and their relationship to the embryonic progenitors of the ENS are currently unknown. Using genetic fate mapping, we here demonstrate that mouse neural crest cells marked by SRY box-containing gene 10 (Sox10) generate the neuronal and glial lineages of enteric ganglia. Most neurons originated from progenitors residing in the gut during mid-gestation. Afterward, enteric neurogenesis was reduced, and it ceased between 1 and 3 months of postnatal life. Sox10-expressing cells present in the myenteric plexus of adult mice expressed glial markers, and we found no evidence that these cells participated in neurogenesis under steady-state conditions. However, they retained neurogenic potential, as they were capable of generating neurons with characteristics of enteric neurons in culture. Furthermore, enteric glia gave rise to neurons in vivo in response to chemical injury to the enteric ganglia. Our results indicate that despite the absence of constitutive neurogenesis in the adult gut, enteric glia maintain limited neurogenic potential, which can be activated by tissue dissociation or injury.

The aryl hydrocarbon receptor (AHR) recognises xenobiotics as well as natural compounds such as tryptophan metabolites, dietary components and microbiota-derived factors1–4 and is important for maintenance of homeostasis at mucosal surfaces. AHR activation induces cytochrome P4501 (CYP1) enzymes, which oxygenate AHR ligands, leading to their metabolic clearance and detoxification5. Thus, CYP1 enzymes appear to play an important feedback role that curtails the duration of AHR signalling6, but it remains elusive whether they also regulate AHR ligand availability in vivo. Here we show that dysregulated expression of Cyp1a1 depletes the reservoir of natural AHR ligands, generating a quasi AHR-deficient state. Constitutive expression of Cyp1a1 throughout the body or restricted specifically to intestinal epithelial cells (IECs) resulted in loss of AHR-dependent type 3 innate lymphoid cells (ILC3) and T helper 17 (Th17) cells and increased susceptibility to enteric infection. The deleterious effects of excessive AHR ligand degradation on intestinal immune functions could be counter-balanced by increasing the intake of AHR ligands in the diet. Thus, our data indicate that IECs serve as gatekeepers for the supply of AHR ligands to the host and emphasise the importance of feedback control in modulating AHR pathway activation.

Homing of hematopoietic stem cells (HSCs) into hematopoietic organs is a prerequisite for the establishment of hematopoiesis during embryogenesis and after bone marrow transplantation. We show that beta1 integrin-deficient HSCs from the para-aortic splanchnopleura and the fetal blood had hematolymphoid differentiation potential in vitro and in fetal organ cultures but were unable to seed fetal and adult hematopoietic tissues. Adult beta1 integrin null HSCs isolated from mice carrying loxP-tagged beta1 integrin alleles and ablated for beta1 integrin expression by retroviral cre transduction failed to engraft irradiated recipient mice. Moreover, absence of beta1 integrin resulted in sequestration of HSCs in the circulation and their reduced adhesion to endothelioma cells. These findings define beta1 integrin as an essential adhesion receptor for the homing of HSCs.