Impacts of the water framework directive on learning and knowledge practices in a Swedish catchment.

Catchments are complex social-ecological systems involving multiple, and often competing, interests. Water governance and management regimes are increasingly embracing pluralistic, participatory, and holistic norms as a means to engage with issues of complexity, uncertainty, and value-conflicts. Integrated, participatory approaches are theoretically linked to improved learning amongst stakeholders across sectors and decision-making that is grounded in shared knowledge, experiences and scientific evidence. However, few studies have empirically examined the impacts of an integrated approach to learning and knowledge practices related to water resources. Here, a Swedish sub-catchment that has adopted such an approach in association with implementation of the European Water Framework Directive (WFD) is examined. Interview-based analyses show that WFD implementation has both helped and hindered learning and knowledge practices surrounding both water planning and spatial planning. Whilst communities of practice have developed in the study area, a number of important challenges remain. These include the rigid goal-orientation of the WFD, the fragmentation of knowledge caused by an over-reliance on external consultants, as well as a lack of resources to synthesise information from multiple sources. Present results raise questions regarding the efficacy of the WFD to sufficiently enable the development of learning and knowledge practices capable of handling the complexity, uncertainties and value-conflicts facing catchments in Sweden and elsewhere.

Governance and management dynamics of landscape restoration at multiple scales: Learning from successful environmental managers in Sweden.

Due to a long history of intensive land and water use, habitat networks for biodiversity conservation are generally degraded in Sweden. Landscape restoration (LR) is an important strategy for achieving representative and functional green infrastructures. However, outcomes of LR efforts are poorly studied, particularly the dynamics of LR governance and management. We apply systems thinking methods to a series of LR case studies to analyse the causal structures underlying LR governance and management in Sweden. We show that these structures appear to comprise of an interlinked system of at least three sets of drivers and four core processes. This system exhibits many characteristics of a transformative change towards an integrated, adaptive approach to governance and management. Key challenges for Swedish LR projects relate to institutional and regulatory flexibility, the timely availability of sufficient funds, and the management of learning and knowledge production processes. In response, successful project leaders develop several key strategies to manage complexity and risk, and enhance perceptions of the attractiveness of LR projects.

STAT1 Signaling in Astrocytes Is Essential for Control of Infection in the Central Nervous System.

The local production of gamma interferon (IFN-γ) is important to control Toxoplasma gondii in the brain, but the basis for these protective effects is not fully understood. The studies presented here reveal that the ability of IFN-γ to inhibit parasite replication in astrocytes in vitro is dependent on signal transducer and activator of transcription 1 (STAT1) and that mice that specifically lack STAT1 in astrocytes are unable to limit parasite replication in the central nervous system (CNS). This susceptibility is associated with a loss of antimicrobial pathways and increased cyst formation in astrocytes. These results identify a critical role for astrocytes in limiting the replication of an important opportunistic pathogen. IMPORTANCE: Astrocytes are the most numerous cell type in the brain, and they are activated in response to many types of neuroinflammation, but their function in the control of CNS-specific infection is unclear. The parasite Toxoplasma gondii is one of the few clinically relevant microorganisms that naturally infects astrocytes, and the studies presented here establish that the ability of astrocytes to inhibit parasite replication is essential for the local control of this opportunistic pathogen. Together, these studies establish a key role for astrocytes as effector cells and in the coordination of many aspects of the protective immune response that operates in the brain.

Cutting Edge: IL-4, IL-21, and IFN-γ Interact To Govern T-bet and CD11c Expression in TLR-Activated B Cells.

T-bet and CD11c expression in B cells is linked with IgG2c isotype switching, virus-specific immune responses, and humoral autoimmunity. However, the activation requisites and regulatory cues governing T-bet and CD11c expression in B cells remain poorly defined. In this article, we reveal a relationship among TLR engagement, IL-4, IL-21, and IFN-γ that regulates T-bet expression in B cells. We find that IL-21 or IFN-γ directly promote T-bet expression in the context of TLR engagement. Further, IL-4 antagonizes T-bet induction. Finally, IL-21, but not IFN-γ, promotes CD11c expression independent of T-bet. Using influenza virus and Heligmosomoides polygyrus infections, we show that these interactions function in vivo to determine whether T-bet(+) and CD11c(+) B cells are formed. These findings suggest that T-bet(+) B cells seen in health and disease share the common initiating features of TLR-driven activation within this circumscribed cytokine milieu.

The Group 3 Innate Lymphoid Cell Defect in Aryl Hydrocarbon Receptor Deficient Mice Is Associated with T Cell Hyperactivation during Intestinal Infection.

Intestinal infection with the intracellular parasite Toxoplasma gondii results in the translocation of commensal bacteria to peripheral organs and the development of a T cell response specific to the microbiota. In naïve mice, the recently described RORγt+ group 3 innate lymphoid cell (ILC) population plays a critical role in promoting intestinal barrier function and limiting responses to gut-resident commensal bacteria. Given this role for group 3 ILCs, studies were performed to evaluate whether these cells might influence the immune response to mucosal infection with T. gondii. Phenotypic characterization of RORγt+ ILCs in T. gondii infected mice revealed that this population decreased following challenge but the population that remained expressed costimulatory molecules and IL-22. One factor that influences the maintenance of RORγt+ ILCs is the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, and Ahr-/- mice have a marked defect in the lamina propria group 3 ILC population. When Ahr-/- mice were challenged with T. gondii, they lost more weight than wild type controls. This disease course in Ahr-/- animals was associated with increased T cell responses to Toxoplasma antigen and crude commensal antigen preparations. Together, these data suggest that group 3 ILCs have a role in limiting T cell activation during intestinal infection.

Bystander chronic infection negatively impacts development of CD8(+) T cell memory.

Epidemiological evidence suggests that chronic infections impair immune responses to unrelated pathogens and vaccines. The underlying mechanisms, however, are unclear and distinguishing effects on priming versus development of immunological memory has been challenging. We investigated whether bystander chronic infections impact differentiation of memory CD8(+) T cells, the hallmark of protective immunity against intracellular pathogens. Chronic bystander infections impaired development of memory CD8(+) T cells in several mouse models and humans. These effects were independent of initial priming and were associated with chronic inflammatory signatures. Chronic inflammation negatively impacted the number of bystander CD8(+) T cells and their memory development. Distinct underlying mechanisms of altered survival and differentiation were revealed with the latter regulated by the transcription factors T-bet and Blimp-1. Thus, exposure to prolonged bystander inflammation impairs the effector to memory transition. These data have relevance for immunity and vaccination during persisting infections and chronic inflammation.

IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms.

Parasitic helminths are a major cause of chronic human disease, affecting more than 3 billion people worldwide. Host protection against most parasitic helminths relies upon Type 2 cytokine production, but the mechanisms that regulate interleukin (IL) 4 and 13 production from CD4(+) T helper 2 cells (T(H)2) and innate lymphoid type 2 cells (ILC2s) remain incompletely understood. The epithelial cell-derived cytokines IL-25 and IL-33 promote Type 2 responses, but the extent of functional redundancy between these cytokines is unclear and whether Type 2 memory relies upon either IL-25 or IL-33 is unknown. Herein, we demonstrate a pivotal role for IL-33 in driving primary and anamnestic immunity against the rodent hookworm Nippostrongylus brasiliensis. IL-33-deficient mice have a selective defect in ILC2-derived IL-13 during both primary and secondary challenge infections but generate stronger canonical CD4(+) T helper 2 cells responses (IL-4, IgE, mast cells, and basophils) than WT controls. Lack of IL-13 production in IL-33-deficient mice impairs resistin-like molecule beta (RELMß) expression and eosinophil recruitment, which are two mechanisms that eliminate N. brasiliensis parasites from infected hosts. Thus, IL-33 is requisite for IL-13 but not IL-4-driven Type 2 responses during hookworm infection.

TGF-ß-responsive myeloid cells suppress type 2 immunity and emphysematous pathology after hookworm infection.

Transforming growth factor ß (TGF-ß) regulates inflammation, immunosuppression, and wound-healing cascades, but it remains unclear whether any of these functions involve regulation of myeloid cell function. The present study demonstrates that selective deletion of TGF-ßRII expression in myeloid phagocytes i) impairs macrophage-mediated suppressor activity, ii) increases baseline mRNA expression of proinflammatory chemokines/cytokines in the lung, and iii) enhances type 2 immunity against the hookworm parasite Nippostrongylus brasiliensis. Strikingly, TGF-ß-responsive myeloid cells promote repair of hookworm-damaged lung tissue, because LysM(Cre)TGF-ßRII(flox/flox) mice develop emphysema more rapidly than wild-type littermate controls. Emphysematous pathology in LysM(Cre)TGF-ßRII(flox/flox) mice is characterized by excessive matrix metalloprotease (MMP) activity, reduced lung elasticity, increased total lung capacity, and dysregulated respiration. Thus, TGF-ß effects on myeloid cells suppress helminth immunity as a consequence of restoring lung function after infection.