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Cytokines produced by immune cells contribute to the development and perpetuation of inflammatory bowel disease (IBD), namely Crohn’s disease and ulcerative colitis, by regulating various aspects of the inflammatory response. Pro-inflammatory cytokines trigger chronic intestinal inflammation, tissue damage, carcinogenesis and perpetuation of disease and suppress the resolution of inflammation in IBD. The clinical success of antibodies that neutralize tumour necrosis factor (TNF) and the cytokine IL-12p40 in individuals with IBD has underscored this concept. Moreover, genetic and preclinical studies have emphasized the crucial role of IL-23 in IBD, leading to clinical approval of antibodies targeting this cytokine. Multiple studies have also investigated the administration of cytokines with assumed anti-inflammatory effects, but this approach has yet to show any real clinical benefit in individuals with IBD. Recent studies have targeted the cytokine network through the use of multi-cytokine blockers (for example, Janus kinase (JAK) inhibitors), IL-2-induced regulatory T cells or advanced combination therapies that use multiple cytokine blockers simultaneously (for example, anti-TNF along with anti-IL-23 antibodies). This Review will focus on our current understanding of how cytokines produced by innate and adaptive immune cells contribute to IBD pathogenesis and discuss how their modulation may inform future treatments for IBD.This Review explains how cytokines contribute to the pathogenesis of inflammatory bowel disease (IBD). The author highlights the cytokine-targeting drugs that are already being successfully used in the clinic and discusses the potential of other cytokine-modulating drugs in IBD.

Mingfu Gong, Department of Radiology, Xinqiao Hospital, Army Medical University, 183 Xinqiao Main Street, Shapingba District, Chongqing, 400037, People’s Republic of China, Email hummer198625@tmmu.cdu.cn Ru Peng Wang, Department of Rheumatology and Dermatology, Xinqiao Hospital, Army Medical University, 183 Xinqiao Main Street, Shapingba District, Chongqing, 400037, People’s Republic of China, Email Wrp71@tmmu.edu.cnBackground: Atopic dermatitis (AD) severely impairs the lives of patients and existing therapies are limited by side effects or insufficient efficacy. In this study, we developed a multifunctional nanocomposite hydrogel that integrates immunoregulation, antioxidant, antibacterial, and skin repair for the integrative treatment of AD.Methods: Fe3O4-Aushell (FA) nanoparticles (NPs) were synthesized, melittin (MLT) was anchored onto FA NPs, and MLT-Fe3O4-Aushell (MFA) was loaded into Pluronic F-127 (PF127), to prepare the MFA@PF127 hydrogel. After a comprehensive evaluation of the physicochemical properties, MFA@PF127 was incubated with HaCaT cells and administered to AD lesions to demonstrate its therapeutic efficiency for AD in vitro and in vivo.Results: The Fe3O4‑Aushell (FA) NPs with a heterodimer morphology and uniform size were successfully prepared, and the MLT was then loaded onto FA NPs with a high loading efficiency of 64.5%. By loading MLT-FA (MFA) NPs into PF127, the MFA@PF127 nanocomposite hydrogel with thermosensitivity, a porous structure, and good biocompatibility was successfully constructed. After incubation with MFA@PF127 and irradiated with near-infrared (NIR) laser, HaCaT cells showed significantly lower thymic stromal lymphopoietin (TSLP) expression and reactive oxygen species (ROS) levels than the control. The growth of S. aureus and biofilm formation were suppressed by MFA@PF127 under NIR irradiation. When administered to AD lesions, MFA@PF127+NIR significantly alleviated the dermatitis severity score; downregulated TSLP, IL‑4, and IL‑13 expression, suppressed S. aureus colonization; reduced ROS levels; and alleviated epidermal thickening and mast cell infiltration.Conclusion: MFA@PF127 exhibited multifunctionality of immunoregulation, and antioxidant and antibacterial activities, which significantly alleviated AD symptoms in a mouse model and provided a potential strategy for AD treatment after further preclinical validation.

Immune responses are governed by signals from the tissue microenvironment, and in addition to biochemical signals, mechanical cues and forces arising from the tissue, its extracellular matrix and its constituent cells shape immune cell function. Indeed, changes in biophysical properties of tissue alter the mechanical signals experienced by cells in many disease conditions, in inflammatory states and in the context of ageing. These mechanical cues are converted into biochemical signals through the process of mechanotransduction, and multiple pathways of mechanotransduction have been identified in immune cells. Such pathways impact important cellular functions including cell activation, cytokine production, metabolism, proliferation and trafficking. Changes in tissue mechanics may also represent a new form of ‘danger signal’ that alerts the innate and adaptive immune systems to the possibility of injury or infection. Tissue mechanics can change temporally during an infection or inflammatory response, offering a novel layer of dynamic immune regulation. Here, we review the emerging field of mechanoimmunology, focusing on how mechanical cues at the scale of the tissue environment regulate immune cell behaviours to initiate, propagate and resolve the immune response.This Review considers how the biophysical properties of a tissue are able to shape immune cell function through the process of mechanotransduction. There are multiple mechanotransduction pathways that operate in immune cells and the authors highlight these and the emerging field of mechanoimmunology.

LKB1 protects regulatory T cells from exhaustion, allowing them to efficiently control T helper 2 cell responses.

IL-17 cytokine family members have diverse biological functions, promoting protective immunity against many pathogens but also driving inflammatory pathology during infection and autoimmunity. IL-17A and IL-17F are produced by CD4+ and CD8+ T cells, γδ T cells, and various innate immune cell populations in response to IL-1β and IL-23, and they mediate protective immunity against fungi and bacteria by promoting neutrophil recruitment, antimicrobial peptide production and enhanced barrier function. IL-17-driven inflammation is normally controlled by regulatory T cells and the anti-inflammatory cytokines IL-10, TGFβ and IL-35. However, if dysregulated, IL-17 responses can promote immunopathology in the context of infection or autoimmunity. Moreover, IL-17 has been implicated in the pathogenesis of many other disorders with an inflammatory basis, including cardiovascular and neurological diseases. Consequently, the IL-17 pathway is now a key drug target in many autoimmune and chronic inflammatory disorders; therapeutic monoclonal antibodies targeting IL-17A, both IL-17A and IL-17F, the IL-17 receptor, or IL-23 are highly effective in some of these diseases. However, new approaches are needed to specifically regulate IL-17-mediated immunopathology in chronic inflammation and autoimmunity without compromising protective immunity to infection.IL-17 cytokines drive biological responses that protect the host against many infections but can also contribute to host pathology in the context of infection and autoimmunity. Here, Kingston Mills highlights the different cellular sources of IL-17 and compares the pathological versus protective functions of these cytokines.

T-bet+ regulatory T cells form a stable subset with specific suppressive activity towards T-bet+effector T cells.

Rheumatoid arthritis (RA) is characterized by inflammation and destruction of bone and cartilage in affected joints. Autoimmune responses lead to increased osteoclastic bone resorption and impaired osteoblastic bone formation, the imbalance of which underlies bone loss in RA, which includes bone erosion, periarticular bone loss and systemic osteoporosis. The crucial role of osteoclasts in bone erosion has been demonstrated in basic studies as well as by the clinical efficacy of antibodies targeting RANKL, an important mediator of osteoclastogenesis. Synovial fibroblasts contribute to joint damage by stimulating both pro-inflammatory and tissue-destructive pathways. New technologies, such as single-cell RNA sequencing, have revealed the heterogeneity of synovial fibroblasts and of immune cells including T cells and macrophages. To understand the mechanisms of bone damage in RA, it is important to clarify how the immune system promotes the tissue-destructive properties of synovial fibroblasts and influences bone cells. The interaction between immune cells and fibroblasts underlies the imbalance between regulatory T cells and T helper 17 cells, which in turn exacerbates not only inflammation but also bone destruction, mainly by promoting RANKL expression on synovial fibroblasts. An improved understanding of the immune mechanisms underlying joint damage and the interplay between the immune system, synovial fibroblasts and bone will contribute to the identification of novel therapeutic targets in RA.In this Review, the authors provide an overview of the mechanisms contributing to joint damage in rheumatoid arthritis, particularly the interactions among immune cells, fibroblasts and bone, and discuss how this knowledge could inform the development of novel therapies.

CD8 + T cells are critical for elimination of cancer cells. Factors within the tumor microenvironment (TME) can drive these cells to a hypofunctional state known as exhaustion. The most terminally exhausted T (tT ex ) cells are resistant to checkpoint blockade immunotherapy and might instead limit immunotherapeutic efficacy. Here we show that intratumoral CD8 + tT ex cells possess transcriptional features of CD4 + Foxp3 + regulatory T cells and are similarly capable of directly suppressing T cell proliferation ex vivo. tT ex cell suppression requires CD39, which generates immunosuppressive adenosine. Restricted deletion of CD39 in endogenous CD8 + T cells resulted in slowed tumor progression, improved immunotherapy responsiveness and enhanced infiltration of transferred tumor-specific T cells. CD39 is induced on tT ex cells by tumor hypoxia, thus mitigation of hypoxia limits tT ex suppression. Together, these data suggest tT ex cells are an important regulatory population in cancer and strategies to limit their generation, reprogram their immunosuppressive state or remove them from the TME might potentiate immunotherapy. Exhausted CD8 + T cells with diminished effector functions accumulate in tumors. Here, the authors show that hypoxia induces a suppressive phenotype in exhausted T cells and that interfering with hypoxia-mediated CD39 expression limits immunosuppression in the tumor and augments immunotherapy, resulting in arrest of tumor growth.

Tumours display an astonishing variation in the spatial distribution, composition and activation state of immune cells, which impacts their progression and response to immunotherapy. Shedding light on the mechanisms that govern the diversity and function of immune cells in the tumour microenvironment will pave the way for the development of more tailored immunomodulatory strategies for the benefit of patients with cancer. Cancer cells, by virtue of their paracrine and juxtacrine communication mechanisms, are key contributors to intertumour heterogeneity in immune contextures. In this Review, we discuss how cancer cell-intrinsic features, including (epi)genetic aberrations, signalling pathway deregulation and altered metabolism, play a key role in orchestrating the composition and functional state of the immune landscape, and influence the therapeutic benefit of immunomodulatory strategies. Moreover, we highlight how targeting cancer cell-intrinsic parameters or their downstream immunoregulatory pathways is a viable strategy to manipulate the tumour immune milieu in favour of antitumour immunity.This Review outlines how the profound intertumoural heterogeneity in immune landscapes of tumours is shaped by cancer cell-intrinsic alterations and highlights how the crosstalk between these two continuously evolving systems not only challenges therapy success of immunomodulatory drugs but also provides the basis for new therapeutic strategies to overcome immune evasion.

Naive T cells are actively maintained in a quiescent state that promotes their survival and persistence. On antigen stimulation, T cells exit quiescence to initiate clonal expansion and effector differentiation. Initial studies focused on the immune receptors and transcriptional regulators involved in T cell quiescence and activation, but recent findings highlight cell metabolism as a crucial regulator of these processes. Here we summarize these intrinsic metabolic programmes and also describe how cell-extrinsic factors, such as nutrients and regulatory T cells, directly and indirectly balance quiescence and activation programmes in conventional T cells. We propose that immunological cues and nutrients license and tune metabolic programmes and signalling networks that communicate in a bidirectional manner to promote quiescence exit. Understanding the programmes that regulate T cell quiescence will be key for developing novel approaches to modulate protective and pathological T cell responses in human diseases.