ON THE COVER
Immune cells produce and secrete cytokines, soluble messengers that regulate the immune system and can act in an autocrine, paracrine, or endocrine manner. The figure depicts immune cell associates as a group of immune cells with trucks delivering cytokines from the immune cells to their targets. Figure by Neil Smith, email@example.com.
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Specific IL-1 family cytokines are initially expressed as inactive, cytosolic pro-forms. Chan and Schroder review inflammasome signaling and cell death decisions, mechanisms underpinning IL-1α, IL-1β, IL-18, and IL-37 maturation and release, and the functions of these cytokines in protective and pathological inflammation.
Distinctions in the nature and spatiotemporal expression of IL-2R subunits on conventional versus regulatory T cells are exploited to manipulate IL-2 immunomodulatory effects. Particularly, low-dose IL-2 and some recombinant derivatives are being evaluated to enhance/inhibit immune responses for therapeutic purposes.
GM-CSF is a potential therapeutic target in inflammation and autoimmunity. This study reviews the literature on the biology of GM-CSF, in particular that describing the research leading to clinical trials targeting GM-CSF and its receptor in numerous inflammatory/autoimmune conditions, such as rheumatoid arthritis.
The authors review the molecular mechanisms regulating IL-10 production and response and describe classic and novel functions of IL-10 in immune and non-immune cells. They further discuss the therapeutic potential of IL-10 in different diseases and the outstanding questions underlying an effective application of IL-10 in clinical settings.
Although many chronic inflammatory diseases share the feature of elevated IL-17 production, therapeutic targeting of IL-17 has vastly different clinical outcomes. Here the authors summarize the recent progress in understanding the protective and pathogenic role of the IL-23/IL-17 axis in preclinical models and human inflammatory diseases.
Interleukin-17 cytokines: Effectors and targets in psoriasis—A breakthrough in understanding and treatment
This review summarizes the steps from basic research on IL-17 family cytokines to understanding their role in psoriasis pathogenesis to the approval of a number of monoclonal antibodies targeting IL-17 pathways as first line treatment of psoriasis and psoriatic arthritis.
This review discusses the growing literature on the pathogenic role of IL-17 in cancer, focusing on recent studies that place IL-17 as a nexus linking inflammation, tissue repair, and cancer.
IL-17 plays versatile roles during tumorigenesis. Here, Vitiello and Miller summarize current knowledge in harnessing IL-17–producing γδ and Th17 cells for successful cancer immunotherapy.
Interleukin-15 (dys)regulation of lymphoid homeostasis: Implications for therapy of autoimmunity and cancer
IL-15 supports NK, NK-T, γδ, ILC1, and memory CD8 T cell function, and dysregulated IL-15 is associated with many autoimmune diseases. Striking IL-15–driven increases in NK and CD8 T cells in patients highlight the potential for combination therapy of cancers.
Here we review the critical and non-redundant functions of IL-21 in regulating humoral immune responses. We particularly focus on studies in natura—from individuals from inborn errors of immunity that impact on IL-21 production and/or function.
Type III IFNs, or IFN-λ, are the latest addition to the IFN family. Thanks to a restricted pattern of expression of their receptor and to unique immunomodulatory properties, IFN-λ stimulates pathogen clearance while, at the same time, curbing inflammation to maintain barrier integrity.
This review summarizes our current understanding of how specific cytokines produced by pathogenic CD4 T cells contribute to central nervous system autoimmune disease. Data obtained from animal models and patients with multiple sclerosis are discussed.
Brief Definitive Reports
Bcl11b binds to distinctive genomic regions with different partners and regulates completely different target genes in pro-T and ILC2 cells. Despite these divergences in Bcl11b function, a shared enhancer supports initial Bcl11b locus opening in both pro-T and ILC2 lineages.
Rag GTPase–dependent nutrient mTORC1 signaling plays a critical role in control of T reg cell suppression of autoimmunity and tumor immunity. These findings establish nutrients as a novel class of signaling molecule.
Endothelial Cdk5 deficit leads to the development of spontaneous epilepsy through CXCL1/CXCR2-mediated reactive astrogliosis
Liu et al. reveal a key mechanism that mediating the transition from cerebrovascular damage to epilepsy. They identify the endothelial cyclin-dependent kinase 5 (CDK5) regulates astrocytic glutamate reuptake and increased glutamate synaptic function through CXCL1/CXCR2-mediated astrogliosis.
The transcription factor c-Maf is an essential regulator of group 3 ILC homeostasis and effector plasticity. c-Maf limits acquisition of the type 1 program and conversion to the ILC1 fate through restraint of T-bet expression and function.
AP-1 transcription factor is recruited to the majority of chromatin remodeling sites during T cell activation. The activity of AP-1 is induced by co-stimulation and is required for chromatin opening. The sites of remodeling overlap with risk loci of immunological diseases.
Regulation of Bcl6 expression during follicular helper T cell differentiation remains incompletely understood. Here, Long et al. show that T cell activation induces H3K36me2 methyltransferase Nsd2, in a CD28- and ICOS-dependent manner, to promote Bcl6 expression and Tfh differentiation.
Developmental and cellular age direct conversion of CD4+ T cells into RORγ+ or Helios+ colon Treg cells
Using a polyclonal Treg cell replacement system, Pratama et al. show that naive Tconv cells have the capacity to convert into both RORγ+ and Helios+ Treg cells in the colon. The developmental maturity (or cell states) of the starting Tconv cells determines the phenotype of the resulting pTreg cells.
CRISPR-mediated disruption of a mosquito gene, mosGILT, impairs ovarian development and vitellogenesis, resulting in enhanced anti-Plasmodium immunity in the malaria vector Anopheles gambiae.
This work identifies an integrin-dependent tissue niche that supports both collective invasion and radiation resistance and can be eradicated by joint targeting of β1 and αV integrins, but neither alone. The additive effect of multiple-integrin interference indicates that clinical efficacy of integrin-based therapy will depend on multi-integrin-targeted strategies.
Mucin-type O-glycans (O-glycans) are a major component of gastric mucus with an unclear function. Liu et al. reports that O-glycans protect gastric mucosa from inflammation and cancer mediated by activation of caspases 1 and 11–dependent inflammasome.