The discovery of interleukin (IL)-6 and its receptor subunits provided a foundation to understand the biology of a group of related cytokines: IL-12, IL-23, and IL-27. These family members utilize ...shared receptors and cytokine subunits and influence the outcome of cancer, infection, and inflammatory diseases. Consequently, many facets of their biology are being therapeutically targeted. Here, we review the landmark discoveries in this field, the combinatorial biology inherent to this family, and how patient datasets have underscored the critical role of these pathways in human disease. We present significant knowledge gaps, including how similar signals from these cytokines can mediate distinct outcomes, and discuss how a better understanding of the biology of the IL-12 family provides new therapeutic opportunities.
The IL-12 family of cytokines influences the outcome of cancer, infection, and inflammatory diseases. Stumhofer, Hunter, and Tait review the combinatorial biology inherent to this family and the recent clinical insights that underscore the critical role of these pathways in human disease.
Innate lymphoid cells (ILCs) are innate immune cells that are ubiquitously distributed in lymphoid and nonlymphoid tissues and enriched at mucosal and barrier surfaces. Three major ILC subsets are ...recognized in mice and humans. Each of these subsets interacts with innate and adaptive immune cells and integrates cues from the epithelium, the microbiota, and pathogens to regulate inflammation, immunity, tissue repair, and metabolic homeostasis. Although intense study has elucidated many aspects of ILC development, phenotype, and function, numerous challenges remain in the field of ILC biology. In particular, recent work has highlighted key new questions regarding how these cells communicate with their environment and other cell types during health and disease. This review summarizes new findings in this rapidly developing field that showcase the critical role ILCs play in directing immune responses through their ability to interact with a variety of hematopoietic and nonhematopoietic cells. In addition, we define remaining challenges and emerging questions facing the field. Finally, this review discusses the potential application of basic studies of ILC biology to the development of new treatments for human patients with inflammatory and infectious diseases in which ILCs play a role.
Innate lymphoid cells (ILCs) are a recently described group of innate immune cells that can regulate immunity, inflammation, and tissue repair in multiple anatomical compartments, particularly the ...barrier surfaces of the skin, airways, and intestine. Broad categories of ILCs have been defined based on transcription factor expression and the ability to produce distinct patterns of effector molecules. Recent studies have revealed that ILC populations can regulate commensal bacterial communities, contribute to resistance to helminth and bacterial pathogens, promote inflammation, and orchestrate tissue repair and wound healing. This review will examine the phenotype and function of murine and human ILCs and discuss the critical roles these innate immune cells play in health and disease.
Group 2 innate lymphoid cells (ILC2s) regulate tissue inflammation and repair after activation by cell-extrinsic factors such as host-derived cytokines. However, the cell-intrinsic metabolic pathways ...that control ILC2 function are undefined. Here we demonstrate that expression of the enzyme arginase-1 (Arg1) during acute or chronic lung inflammation is a conserved trait of mouse and human ILC2s. Deletion of mouse ILC-intrinsic Arg1 abrogated type 2 lung inflammation by restraining ILC2 proliferation and dampening cytokine production. Mechanistically, inhibition of Arg1 enzymatic activity disrupted multiple components of ILC2 metabolic programming by altering arginine catabolism, impairing polyamine biosynthesis and reducing aerobic glycolysis. These data identify Arg1 as a key regulator of ILC2 bioenergetics that controls proliferative capacity and proinflammatory functions promoting type 2 inflammation.
Chemokines have a central role in regulating processes essential to the immune function of T cells, such as their migration within lymphoid tissues and targeting of pathogens in sites of ...inflammation. Here we track T cells using multi-photon microscopy to demonstrate that the chemokine CXCL10 enhances the ability of CD8+ T cells to control the pathogen Toxoplasma gondii in the brains of chronically infected mice. This chemokine boosts T-cell function in two different ways: it maintains the effector T-cell population in the brain and speeds up the average migration speed without changing the nature of the walk statistics. Notably, these statistics are not Brownian; rather, CD8+ T-cell motility in the brain is well described by a generalized Lévy walk. According to our model, this unexpected feature enables T cells to find rare targets with more than an order of magnitude more efficiency than Brownian random walkers. Thus, CD8+ T-cell behaviour is similar to Lévy strategies reported in organisms ranging from mussels to marine predators and monkeys, and CXCL10 aids T cells in shortening the average time taken to find rare targets.
Helminths make themselves at home Tait Wojno, Elia D
The Journal of experimental medicine,
01/2022, Letnik:
219, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Drurey et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20211140) show that excretory/secretory products from the parasitic helminth Heligmosomoides polygyrus suppress the host-protective small ...intestinal epithelial response. These findings establish that helminths directly modulate the tissue in which they live, shining new light on the host-parasite interaction.
Type 2 immunity is critical for the protective and repair responses that mediate resistance to parasitic helminth infection. This immune response also drives aberrant inflammation during atopic ...diseases. Prostaglandins are a class of critical lipid mediators that are released during type 2 inflammation and are integral in controlling the initiation, activation, maintenance, effector functions, and resolution of Type 2 inflammation. In this review, we explore the roles of the different prostaglandin family members and the receptors they bind to during allergen‐ and helminth‐induced Type 2 inflammation and the mechanism through which prostaglandins promote or suppress Type 2 inflammation. Furthermore, we discuss the potential role of prostaglandins produced by helminth parasites in the regulation of host–pathogen interactions, and how prostaglandins may regulate the inverse relationship between helminth infection and allergy. Finally, we discuss opportunities to capitalize on our understanding of prostaglandin pathways to develop new therapeutic options for humans experiencing Type 2 inflammatory disorders that have a significant prostaglandin‐driven component including allergic rhinitis and asthma.
Prostaglandins are critical regulators of the Type 2 immune response that occurs in response to parasitic helminth infection or exposure to allergens. These bioactive lipids control the initiation, activation, maintenance, effector functions, and resolution of Type 2 inflammation and can be pro‐ or anti‐inflammatory. As such, prostaglandins produced by hosts or helminth parasites could be targeted to treat humans with Type 2 inflammatory disorders.
Background:
Infiltration of cluster of differentiation (CD) 3+ (CD3+) T cells into the synovium and synovial fluid occurs in most patients with posttraumatic osteoarthritis. During disease ...progression, proinflammatory T helper 17 cells and anti-inflammatory regulatory T cells infiltrate the joint in response to inflammation. This study aimed to characterize the dynamics of regulatory T and T helper 17 cell populations in synovial fluid from equine clinical patients with posttraumatic osteoarthritis to determine whether phenotype and function are associated with potential immunotherapeutic targets.
Hypothesis:
An imbalance of the ratio of regulatory T cells and T helper 17 cells would be associated with disease progression in posttraumatic osteoarthritis, suggesting opportunities for immunomodulatory therapy.
Study Design:
Descriptive laboratory study.
Methods:
Synovial fluid was aspirated from the joints of equine clinical patients undergoing arthroscopic surgery for posttraumatic osteoarthritis resulting from intra-articular fragmentation. Joints were classified as having mild or moderate posttraumatic osteoarthritis. Synovial fluid was also obtained from nonoperated horses with normal cartilage. Peripheral blood was obtained from horses with normal cartilage and those with mild and moderate posttraumatic osteoarthritis. Synovial fluid and peripheral blood cells were analyzed by flow cytometry, and native synovial fluid was analyzed by enzyme-linked immunosorbent assay.
Results:
CD3+ T cells represented 81% of lymphocytes in synovial fluid, which increased in animals with moderate posttraumatic osteoarthritis to 88.3% (P = .02). CD14+ macrophages were doubled in those with moderate posttraumatic osteoarthritis compared with mild posttraumatic osteoarthritis and controls (P < .001). Less than 5% of CD3+ T cells found within the joint were forkhead box P3 protein+ (Foxp3+) regulatory T cells, but a 4- to 8-times higher percentage of nonoperated and mild posttraumatic osteoarthritis joint regulatory T cells secreted interleukin (IL)–10 than peripheral blood Tregs (P < .005). T regulatory-1 cells that secreted IL-10 but did not express Foxp3 accounted for approximately 5% of CD3+ T cells in all joints. T helper 17 cells and Th17-like regulatory T cells were increased in those with moderate posttraumatic osteoarthritis (P < .0001) compared with mild and nonoperated patients. IL-10, IL-17A, IL-6, chemokine (C-C motif) ligand (CCL) 2 (CCL2), and CCL5 concentrations detected by enzyme-linked immunosorbent assay in synovial fluid were not different between groups.
Conclusions:
An imbalance of the ratio of regulatory T cells and T helper 17 cells and an increase in T helper 17 cell–like regulatory T cells in synovial fluid from joints with more severe disease provide novel insights into immunological mechanisms that are associated with posttraumatic osteoarthritis progression and pathogenesis.
Clinical Relevance:
Early and targeted use of immunotherapeutics in the mitigation of posttraumatic osteoarthritis may improve patient clinical outcomes.
The release of cytokines from epithelial and stromal cells is critical for the initiation and maintenance of tissue immunity. Three such cytokines, thymic stromal lymphopoietin, IL-33, and IL-25, are ...important regulators of type 2 immune responses triggered by parasitic worms and allergens. In particular, these cytokines activate group 2 innate lymphoid cells, TH2 cells, and myeloid cells, which drive hallmarks of type 2 immunity. However, emerging data indicate that these tissue-associated cytokines are not only involved in canonical type 2 responses but are also important in the context of viral infections, cancer, and even homeostasis. Here, we provide a brief review of the roles of thymic stromal lymphopoietin, IL-33, and IL-25 in diverse immune contexts, while highlighting their relative contributions in tissue-specific responses. We also emphasize a biologically motivated framework for thinking about the integration of multiple immune signals, including the 3 featured in this review.
Testing the Larson relations in massive clumps Traficante, A; Duarte-Cabral, A; Elia, D ...
Monthly notices of the Royal Astronomical Society,
06/2018, Letnik:
477, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Abstract
We tested the validity of the three Larson relations in a sample of 213 massive clumps selected from the Herschel infrared Galactic Plane (Hi-GAL) survey, also using data from the Millimetre ...Astronomy Legacy Team 90 GHz (MALT90) survey of 3-mm emission lines. The clumps are divided into five evolutionary stages so that we can also discuss the Larson relations as a function of evolution. We show that this ensemble does not follow the three Larson relations, regardless of the clump's evolutionary phase. A consequence of this breakdown is that the dependence of the virial parameter αvir on mass (and radius) is only a function of the gravitational energy, independent of the kinetic energy of the system; thus, αvir is not a good descriptor of clump dynamics. Our results suggest that clumps with clear signatures of infall motions are statistically indistinguishable from clumps with no such signatures. The observed non-thermal motions are not necessarily ascribed to turbulence acting to sustain the gravity, but they might be a result of the gravitational collapse at the clump scales. This seems to be particularly true for the most massive (M ≥ 1000 M⊙) clumps in the sample, where exceptionally high magnetic fields might not be enough to stabilize the collapse.
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