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Recognition and maturation of IL-18 by caspase-4 noncanonical inflammasome
Activated human caspase-4 directly and efficiently processes IL-18 in vitro and during bacterial infections, cleaving the same tetrapeptide site in pro-IL-18 as caspase-1.
- Xuyan Shi
- , Qichao Sun
- & Feng Shao
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Article |
Epithelial IFNγ signalling and compartmentalized antigen presentation orchestrate gut immunity
IFNγ signalling in epithelial cells promotes antigen presentation that confers intra-epithelial T cells the ability to limit extracellular ATP and consequent NLRP3 inflammasome activation, controlling pathogenic transformation of CD4+ T cells that promotes colitis and colorectal cancer in mouse models.
- Ankit Malik
- , Deepika Sharma
- & Bana Jabri
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Article
| Open Access
Distinguishing features of long COVID identified through immune profiling
Individuals with long COVID show marked biological changes in cortisol and immune factors relative to convalescent populations.
- Jon Klein
- , Jamie Wood
- & Akiko Iwasaki
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Article |
Macrophage fumarate hydratase restrains mtRNA-mediated interferon production
Inhibition of the tricarboxylic acid cycle enzyme fumarate hydratase leads to deregulation of cytokine production in macrophages, which has implications in human diseases such as systemic lupus erythematosus.
- Alexander Hooftman
- , Christian G. Peace
- & Luke A. J. O’Neill
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Article
| Open Access
PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells
Binding of the PD1-IL2v immunocytokine to PD-1 and IL-2Rβγ on the same cell leads to an alternative differentiation of stem-like CD8+ T cells into better effectors rather than exhausted T cells in models of both chronic infection and cancer.
- Laura Codarri Deak
- , Valeria Nicolini
- & Pablo Umaña
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Article |
PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program
PD-1+TCF1+ stem-like CD8+ T cells—precursors of exhausted CD8+ T cells—are not fate-locked into the exhaustion program; their differentiation trajectory can be changed by IL-2 signals.
- Masao Hashimoto
- , Koichi Araki
- & Rafi Ahmed
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Article
| Open Access
Organizing structural principles of the IL-17 ligand–receptor axis
Cryo-electron microscopy structures of IL-25–IL-17RB–IL-17RA and IL-17A–IL-17RC–IL-17RA complexes show a tip-to-tip architecture, which is a key organizing principle of the IL-17 receptor family.
- Steven C. Wilson
- , Nathanael A. Caveney
- & K. Christopher Garcia
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Article
| Open Access
Potentiating adoptive cell therapy using synthetic IL-9 receptors
Synthetic chimeric orthogonal IL-2 receptors that incorporate the intracellular domain of receptors for other γ-chain cytokines such as IL-9 can reroute orthogonal signalling and alter the phenotype of T cells to improve anti-tumour responses.
- Anusha Kalbasi
- , Mikko Siurala
- & K. Christopher Garcia
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Article |
Obesity alters pathology and treatment response in inflammatory disease
Obesity changes the characteristics of the immune response induced in a mouse model of atopic dermatitis, suggesting therapies that could be used against immune dysregulation in obesity.
- Sagar P. Bapat
- , Caroline Whitty
- & Alexander Marson
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Article |
IL-27 signalling promotes adipocyte thermogenesis and energy expenditure
Therapeutic administration of IL-27—serum levels of which are decreased in individuals with obesity—improves thermogenesis, protects against diet-induced obesity and ameliorates insulin resistance in mouse models of obesity.
- Qian Wang
- , Dehai Li
- & Zhinan Yin
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Article |
An engineered IL-2 partial agonist promotes CD8+ T cell stemness
H9T, an engineered IL-2 partial agonist, promotes the expansion of T cells while maintaining a stem-cell-like state, leading to improved efficacy of adoptive cell therapy in mouse models of melanoma and acute lymphoblastic leukaemia.
- Fei Mo
- , Zhiya Yu
- & Warren J. Leonard
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Article |
APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans
The heparan sulfate proteoglycan-binding cytokine APRIL has a protective role against atherosclerotic disease.
- Dimitrios Tsiantoulas
- , Mahya Eslami
- & Christoph J. Binder
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Article |
Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease
Interleukin-3 signalling from astrocytes to microglia readies microglia to defend against Alzheimer’s disease.
- Cameron S. McAlpine
- , Joseph Park
- & Filip K. Swirski
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Article |
Integration of innate immune signalling by caspase-8 cleavage of N4BP1
NEDD4-binding protein 1 (N4BP1) is identified as a suppressor of cytokine production that is inactivated by caspase-8, which provides insight into the mechanisms underlying the immunodeficiency caused by mutations in FADD and caspase-8.
- Alexander D. Gitlin
- , Klaus Heger
- & Vishva M. Dixit
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Article |
Longitudinal analyses reveal immunological misfiring in severe COVID-19
A longitudinal analysis of immune responses in patients with moderate or severe COVID-19 identifies a maladapted immune response profile linked to severe disease.
- Carolina Lucas
- , Patrick Wong
- & Akiko Iwasaki
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Article |
IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy
An engineered version of IL-18 that is resistant to binding by the soluble decoy receptor IL-18BP shows strong anti-tumour activity in mouse models of cancer.
- Ting Zhou
- , William Damsky
- & Aaron M. Ring
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Article |
Sex-specific adipose tissue imprinting of regulatory T cells
Visceral adipose tissue contains populations of regulatory T cells that exhibit sexual dimorphism, determined by the surrounding niche, and differ between male and female mice in terms of cell number, phenotype, transcriptional landscape and chromatin accessibility.
- Ajithkumar Vasanthakumar
- , David Chisanga
- & Axel Kallies
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Article |
Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells
The interleukin-15 superagonist N-803, combined with the depletion of CD8+ lymphocytes, induced a robust and persistent reactivation of the virus in vivo in both antiretroviral-therapy-treated SIV-infected macaques and HIV-infected humanized mice.
- Julia Bergild McBrien
- , Maud Mavigner
- & Guido Silvestri
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Article |
Structure of the IFNγ receptor complex guides design of biased agonists
The X-ray structure of the hexameric complex of interferon-γ bound to its receptors is solved at 3.25 Å resolution, providing a basis for engineering variants of interferon-γ that enable decoupling of its immunomodulatory functions.
- Juan L. Mendoza
- , Nichole K. Escalante
- & K. Christopher Garcia
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Article |
De novo design of potent and selective mimics of IL-2 and IL-15
A hyper-stable de novo protein mimic of interleukin-2 computationally designed to not interact with a regulatory T-cell specific receptor subunit has improved therapeutic activity in mouse models of melanoma and colon cancer.
- Daniel-Adriano Silva
- , Shawn Yu
- & David Baker
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Letter |
Reversing SKI–SMAD4-mediated suppression is essential for TH17 cell differentiation
TGFβ signalling regulates T helper 17 (TH17) cell differentiation by reversing SKI–SMAD4-mediated suppression of RORγt, revealing a potential therapeutic target for treating TH17-related diseases.
- Song Zhang
- , Motoki Takaku
- & Yisong Y. Wan
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Article |
IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses
Interleukin-17 functions as a neuromodulator in the roundworm Caenorhabditis elegans, acting directly on RMG hub interneurons to alter their response properties and contribution to behaviour.
- Changchun Chen
- , Eisuke Itakura
- & Mario de Bono
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Letter |
Tuft-cell-derived IL-25 regulates an intestinal ILC2–epithelial response circuit
Epithelial tuft cells are shown to be the source of intestinal interleukin (IL)-25 that is required for activation of type 2 innate lymphoid cells (ILC2s), ILC2-regulated tuft and goblet cell expansion, and control of parasite infection.
- Jakob von Moltke
- , Ming Ji
- & Richard M. Locksley
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Letter |
Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration
Innate lymphoid cells increase the growth of mouse intestinal organoids via IL-22 production; recombinant IL-22 promotes growth of both mouse and human organoids, and promotes mouse intestinal stem cell (ISC) expansion and ISC-driven organoid growth via a STAT3-dependent pathway and independently of Paneth cells; IL-22 treatment in vivo enhances the recovery of ISCs from intestinal injury.
- Caroline A. Lindemans
- , Marco Calafiore
- & Alan M. Hanash
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Article |
Immune homeostasis enforced by co-localized effector and regulatory T cells
Autoantigen-presenting dendritic cells are shown to interact with both effector and regulatory T cells, and effector-produced IL-2 activates the transcription factor STAT5 in regulatory T cells, which in turn upregulates suppressive molecules and prevents autoimmunity.
- Zhiduo Liu
- , Michael Y. Gerner
- & Ronald N. Germain
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Letter |
Type 2 innate lymphoid cells control eosinophil homeostasis
Eosinophil recruitment to the lung and intestine is regulated by type-2-innate-lymphoid-cell-derived IL-5 and IL-13; IL-5 is shown to be induced by the neuropeptide vasoactive intestinal peptide, which is known to coordinate pancreatic secretion with smooth muscle relaxation in response to feeding.
- Jesse C. Nussbaum
- , Steven J. Van Dyken
- & Richard M. Locksley
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Letter |
M-CSF instructs myeloid lineage fate in single haematopoietic stem cells
M-CSF, a myeloid cytokine released during infection and inflammation, instructs myeloid lineage fate in single haematopoietic stem cells by directly inducing PU.1, a known myeloid lineage master regulator; this shows that specific cytokines can act directly on haematopoietic stem cells to instruct a change of cell identity.
- Noushine Mossadegh-Keller
- , Sandrine Sarrazin
- & Michael H. Sieweke
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Letter |
Interleukin receptor activates a MYD88–ARNO–ARF6 cascade to disrupt vascular stability
Interleukin-1β-induced disruption to endothelial stability and vascular permeability in a human in vitro model is shown to be independent of downstream nuclear factor-κB activation, relying instead on a MYD88–ARNO–ARF6 signalling cascade; inhibiting proteins involved in this pathway is shown to improve outcomes in animal models of inflammatory disease.
- Weiquan Zhu
- , Nyall R. London
- & Dean Y. Li
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Letter |
IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine
IL-22 is one of the factors that, although important for wound healing, also promote tumorigenesis; the regulation of IL-22BP, the IL-22 binding protein, via the NLRP3 and NLRP6 inflammasomes provides an unanticipated mechanism, controlling IL-22 and thereby the development of colon cancer.
- Samuel Huber
- , Nicola Gagliani
- & Richard A. Flavell
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Letter |
A FOXO3–IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses
FOXO3 is a negative regulator of IRF7, a master regulator of the antiviral response.
- Vladimir Litvak
- , Alexander V. Ratushny
- & Alan Aderem
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News |
Genome study highlights risk factor for multiple sclerosis
Discovery of genetic variant could help to improve clinical trials of potential therapies.
- Ewen Callaway
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Letter |
Generalized Lévy walks and the role of chemokines in migration of effector CD8+ T cells
T cells in the brains of Toxoplasma-infected mice are shown to move by Lévy-like walks.
- Tajie H. Harris
- , Edward J. Banigan
- & Christopher A. Hunter
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Letter |
Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1β
Infection with Candida albicans and Staphylococcus aureus gives rise to TH17 cells with different properties; microbe-induced T-cell differentiation is shown here to depend on the balance between polarizing cytokines rather than absolute amounts.
- Christina E. Zielinski
- , Federico Mele
- & Federica Sallusto
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Letter |
Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’
Although IL-2 has been studied for its immune-stimulating activity against metastatic cancer, its side effects have limited its clinical use; here, an engineered IL-2 ‘superkine’ is shown to have increased activity, particularly in inducing antitumour T cells, but fewer side effects.
- Aron M. Levin
- , Darren L. Bates
- & K. Christopher Garcia
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Letter |
Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein
A family of small molecules called ‘ciliobrevins’ are described that can rapidly and reversibly modulate the AAA+ ATPase motor dynein, which transports cargo molecules along microtubule tracks.
- Ari J. Firestone
- , Joshua S. Weinger
- & James K. Chen
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Research Highlights |
Platelets signal cells to invade
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Outlook |
Asthma: Breathing new life into research
Asthma was once thought to be a uniform disease triggered by one type of immune cell. Researchers are now revealing the complexity of the condition and hope to hasten new drugs for forms unresponsive to steroids.
- Amy Maxmen
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Research Highlights |
Calming the cytokine storm
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Letter |
Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis
- Claudia Günther
- , Eva Martini
- & Christoph Becker
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Review Article |
Lessons on the pathogenesis of aneurysm from heritable conditions
- Mark E. Lindsay
- & Harry C. Dietz
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Letter |
A diverse range of gene products are effectors of the type I interferon antiviral response
- John W. Schoggins
- , Sam J. Wilson
- & Charles M. Rice
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Research Highlights |
Immunology: Keeping the peace
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Letter |
RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis
Progestins, used in hormone replacement therapy and contraceptives, have been suggested to promote the development of breast cancer. These authors show that the ability of progestins to induce mammary tumours in mouse models is mediated by RANKL (receptor activator of NF-KB ligand). Inhibition of RANKL could reduce tumorigenesis in hormone-induced and other mouse mammary gland tumour models, suggesting a new therapeutic approach.
- Eva Gonzalez-Suarez
- , Allison P. Jacob
- & William C. Dougall
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Letter |
Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer
Progestins, used in contraceptives and hormone replacement therapy, have been linked to breast cancer. These authors provide a mechanistic basis for this association. They show in a mouse model that synthetic progestins can promote mammary tumour formation by inducing RANKL (receptor activator of NF-KB ligand), which acts on mammary epithelial cells through the RANKL receptor RANK.
- Daniel Schramek
- , Andreas Leibbrandt
- & Josef M. Penninger
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Letter |
Quiescent haematopoietic stem cells are activated by IFN-γ in response to chronic infection
Using a mouse model of Mycobacterium avium infection, it is shown here that interferon-γ regulates the proliferation of primitive haematopoietic cells during chronic infection.
- Megan T. Baldridge
- , Katherine Y. King
- & Margaret A. Goodell
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Letter |
Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology
The cytokine interleukin (IL)-23 has inflammatory effects on innate immune cells and can drive colitis, but the cellular and molecular pathways involved are poorly characterized. Here it is shown that bacterial-driven innate colitis involves a previously unknown population of IL-23-responsive innate leukocytes that produce IL-17 and interferon-γ. These cells may represent a target in inflammatory bowel disease.
- Sofia Buonocore
- , Philip P. Ahern
- & Fiona Powrie
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News & Views |
Close encounters of the second type
To combat intestinal worms, mammals rely on adaptive immune responses mediated by T cells. However, it seems that, initially, innate immune cells mimic T-cell activity, while T cells get ready for action.
- Gérard Eberl
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Letter |
IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses
Several non-haematopoietic-cell-derived cytokines, including interleukin (IL)25, have been implicated in inducing T helper 2 (TH2) cell-dependent inflammation, but their precise role has been unclear. Here, IL25 is shown to promote the accumulation of multipotent progenitor cells in gut-associated lymphoid tissue. These cells can give rise to macrophage or granulocyte lineages that promote the differentiation of TH2 cells and contribute to protective immunity against helminth infections.
- Steven A. Saenz
- , Mark C. Siracusa
- & David Artis
Smoking changes adaptive immunity with persistent effects
Latent TGF-β structure and activation