Cytokines have context-dependent roles that dictate their normal physiological function; however, dysregulation or chronic activation of cytokine pathways can alter tissue balance away from a return to homeostatic quiescence toward disease-associated immunopathology.
Cytokines are chemical cues that instruct the homeostasis and function of immune cells. Whereas proinflammatory cytokines alert the immune system to the presence of potential infection or danger, unregulated cytokine production can lead to autoinflammatory disease states. Nature Immunology presents four Reviews that discuss the regulation of type I interferons, the homeostatic cytokines IL-7 and TSLP and the inflammatory cytokine IL-17, and the implications of this for therapeutic intervention, as well as dysregulation that can lead to disease.
Ivashkiv and colleagues review the mechanisms by which IFN signatures and IFN epigenomic signatures are generated, as well as the functional consequences of these signatures in homeostasis and autoimmune diseases.
Xiaoxia Li and colleagues discuss the roles of signaling via IL-17 and its receptor and the implications of this axis for human health, noting their normal protective roles directed against fungi and bacteria as well as against pathological conditions in inflammation and cancer.
Ziegler and Corren review the cytokine TSLP, which regulates immune cell homeostasis at mucosal barriers, its role in allergic responses and newly discovered roles in cancer.
The cytokine IL-7 plays essential roles in lymphocyte development. In their Review, Barata, Durum and Seddon describe IL-7’s key homeostatic functions and how its dysregulation can lead to autoinflammatory disease and cancer.
From the archive
IL-1R3 blockade broadly attenuates the functions of six members of the IL-1 family, revealing their contribution to models of disease
Multiple cytokines in the proinflammatory IL-1 family share the co-receptor IL-1R3. Dinarello and colleagues show that a fully humanized antibody to IL-1R3 can effectively control inflammation and disease mediated not only by IL-1 but also by IL-33 and IL-36.
Interferon-λ modulates dendritic cells to facilitate T cell immunity during infection with influenza A virus
IFN-λ has important innate immune system functions at mucosal surfaces, but its importance in adaptive immunity is largely unknown. Using an influenza infection model, Gale and colleagues demonstrate that IFN-λ is essential for effective adaptive cellular immunity in the lung.
Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways
Nephritis is a major cause of lupus morbidity. Putterman and colleagues use single-cell RNA sequencing on human renal and skin biopsies to describe the expression landscape associated with lupus nephritis.
IL-17 metabolically reprograms activated fibroblastic reticular cells for proliferation and survival
Fibroblastic reticular cells support lymph-node function and adaptive immunity. McGeachy and colleagues show that the cytokine IL-17 is needed to trigger metabolic changes required for the proliferation and survival of these cells in reactive lymph nodes.
Regulatory T cells obstruct effective anti-cancer immune responses. Vignali and colleagues demonstrate that IL-10 production and IL-35 production by tumor-infiltrating regulatory T cells mediate differential and non-redundant suppressive effects on tumor-reactive cytotoxic T cells.
The role of IFN-λ in adaptive immunity is not well characterized. Staeheli and colleagues show that in the lungs, IFN-λ elicits production of the cytokine TSLP from M cells and that this in turn is essential for effective adaptive immunity and control of infection with influenza virus.
A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape
Interferon-stimulated genes (ISGs) are a key component of the antiviral response. Pichlmair and colleagues generate a comprehensive ISG interactome that sheds light on their functions in antiviral responses.
The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum
STIM1 is a calcium sensor that is essential for functional lymphocyte responses. Gwack and colleagues demonstrate a calcium-independent role for STIM1 in macrophages that regulates their production of type I interferons.
RNAs can be dynamically modified by N6-methylation of adenosine (m6A), which leads to their destabilization. Stern-Ginossar and colleagues demonstrate a role for m6A modification of host transcripts encoding type I interferons during viral infection.
The IL-15–AKT–XBP1s signaling pathway contributes to effector functions and survival in human NK cells
Yu and colleagues show that the transcription factor XBP1s positively regulates the cytolytic activity of human NK cells and is required for the IL-15-mediated survival of NK cells.
PRMT arginine methyltransferases mediate post-translational modification. Takayanagi and colleagues show that a lack of PRMT5 in cells of the T cell lineage compromises their response to cytokines dependent on the common γ-chain, due to aberrant splicing of mRNA transcripts encoding the common γ-chain and its associated kinase JAK3.
The immune response to pathogens varies substantially among humans. Netea and colleagues show that integration of multi-omics data and deep phenotyping enables prediction of cytokine production in responses to pathogens.
γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis
Lynch, Brenner and colleagues find that tissue-resident γδ T cells reside in adipose tissues in both mice and humans. These cells play essential roles in regulating thermogenesis and supporting age-dependent increases in adipose-tissue regulatory T cell populations.
IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling
Act1 is an adaptor protein that associates with the IL-17 receptor at the cell membrane. Li and colleagues show that Act1 also exhibits unexpected RNA-binding activity and directly stabilizes select mRNAs encoding inflammatory cytokines and chemokines.
A tumor–myeloid cell axis, mediated via the cytokines IL-1α and TSLP, promotes the progression of breast cancer
Tumor cells commonly manipulate their environment to ensure their survival. Kuan and Ziegler show that breast cancer cells release IL-1α, which acts on infiltrating myeloid cells to elicit their production of TSLP. In turn, TSLP promotes the survival of TSLPR+ tumor cells by upregulating expression of the pro-survival factor Bcl-2.
Klein and colleagues show, in a mouse model of West Nile virus–induced cognitive dysfunction, that neurogenesis is impaired by production of IL-1 from pro-inflammatory astrocytes.
Cao and colleagues identify the E3 ubiquitin ligase RNF2 as an inhibitor of interferon-dependent antiviral responses that acts by promoting the K33-linked polyubiquitination of STAT1 and its disassociation from DNA.
The cytokine IL-33 has major roles in type 2 immunity and allergy. Girard and colleagues demonstrate that a broad range of allergens across multiple kingdoms can directly cleave IL-33 via their intrinsic protease activity and convert it into a highly active processed form.
The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation
Kastner and colleagues review monogenic autoinflammatory diseases and their molecular mechanisms and explore the overlap among autoinflammation, autoimmunity and immunodeficiency.
Although interleukin 17 (IL-17) has modest activity on its own, it has a substantial impact in immunity through its synergistic action with other factors and its self-sustaining feedback loop. Veldhoen discusses the role of IL-17 during infections.
IL-33 has well-described roles in type 2 immune responses; however, the scope of its functions are rapidly widening. Martin and Martin review the latest knowledge on IL-33 as an alarmin, intracellular molecule and cytokine.
IL-1α is a ubiquitously expressed cytokine that has diverse roles in immunity and homeostasis. Di Paolo and Shayakhmetov review IL-1α's distinctive and important role in inflammation.
Type I and III interferons share similar antiviral properties, but there are some important distinctions. Hartmann and colleagues review the specialized functions of type III interferons, including their ability to mediate antiviral functions at barrier surfaces.
IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. Hunter and Jones discuss the effect of IL-6 on innate and adaptive immunity, and consider how the immunobiology of IL-6 may inform clinical decisions.