Search

Platelets are known to have functions beyond those in thrombosis and haemostasis. Here the authors use multi-colour flow cytometry and proteomics to analyse platelet phenotypes in psoriatic disease and proteins that are potentially involved in the interaction of platelets with immune cells.

Here, Becher and colleagues examine the paradoxical roles of IL-12 and IL-23, two IL-12 family cytokines that drive type 1 and type 3 immune responses, respectively. Both promote inflammation by activating T cells, natural cells and innate lymphoid cells through cytokine polarization, yet IL-12 also supports antitumour immunity and IL-23 maintains barrier integrity. This Review highlights emerging evidence that both cytokines can also dampen immune responses, revealing unexpected regulatory roles in cancer, autoimmunity and tissue homeostasis.

Adipose tissue is composed of a number of adipocytes and a number of other cells including immune cells. Here the authors use single-cell sequencing of murine brown adipose tissue immune cells and describe multiple macrophage and monocyte subsets and show that monocytes contribute to brown adipose tissue expansion.

During development, blood is generated in the yolk sac by differentiation of haemato-endothelial mesoderm into haematopoietic progenitors. Using CRISPR-Cas9 screens, the authors identify Etv2, Smad1, Ldb1, Six4 and Zbtb7b as regulators of haemato-endothelial mesoderm commitment. Lack of these regulators gave rise to mesodermal subsets with a defined lineage differentiation bias.

IL-23 promotes tumor growth in preclinical cancer models and correlates with adverse clinical outcomes. Here, Becher and colleagues find that IL-23 produced by tumor-associated macrophages stabilizes T_reg cell identity, promoting immunosuppression and tumor growth.

Here the authors identify adenophages, a previously unknown macrophage population present in exocrine glands in mice and humans. These cells are dependent on ILC2-derived GM-CSF and support glandular homeostasis.

IL-12 is believed to mediate antitumor activity via NK and T_H1 cells. However, Becher and co-workers now show that IL-12 activates NKp46⁺ lymphoid tissue–inducer cells, which locally modify the tumor environment.

Becher et al. perform a head-to-head comparison of multiple severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) vaccine prime-boost combinations and analyze the ensuing humoral and cellular responses in a large randomized cohort.

Many cancers metastasize to the lungs, yet immune cells rarely succeed in eliminating them. Here we show that although NK cells that patrol the lung vasculature are highly differentiated and cytotoxic to circulating tumor cells, these fail to access extravasated lesions, while NK cells that infiltrate the tumor parenchyma are less differentiated, exhibit poor cytotoxicity functionally restrained by TGF-β, allowing metastatic tumors to persist.

Despite the irrefutable role of inflammation in psoriasis, a complete knowledge of what immune cells and cytokines are involved during initiation and progression of this skin disease is lacking. Moreover, the complexities of the immune cell network and potential differences between mice and humans have led to translational failures. It is therefore important that we acquire in-depth understanding of what inflammatory players, of the many involved, are crucial, if we wish to develop effective therapies. In 'Bedside to Bench', James Krueger discusses how a subset of T cells, T_H17 cells, which release interleukin-17 in humans, seem to be essential for pathogenesis of psoriasis. The interplay between interleukin-17 and other cytokines that may potentially be involved in psoriasis also needs further investigation. Additionally, there are open questions as to what subset of T cells, other than T_H17, also produce interleukin-17 and when. In 'Bench to Bedside', Burkhard Becher and Stanislav Pantelyushin examine this issue by looking at a mouse model of skin inflammation that resembles psoriasis in humans. A class of skin-invading innate immune cells called γδ T cells was shown to drive skin inflammation in this model, particularly during the early stages of the disease, suggesting that innate immunity plays an important part in the initiation of psoriasis.

Interleukin-12 (IL-12) can have anti-inflammatory properties; however, the underlying mechanisms are unclear. Here, the authors show that IL-12-sensing neurons mediate IL-12-induced neuroprotective tissue adaptation in autoimmune conditions of the CNS.

T-cell receptor peptide vaccines may hold promise as future therapy for multiple sclerosis (pages 1109–1115).

The development of experimental autoimmune encephalomyelitis has been attributed to cells of the T_H1 or T_H17 subset of helper T cells. Becher and Rostami and their colleagues show that IL-23-induced production of the cytokine GM-CSF underlies disease development and severity.

Steroid-refractory acute graft-versus-host disease (aGVHD) is associated with a low one-year survival rate. Here, the authors show that ROCK1 is upregulated in leukocytes from patients with steroid-refractory aGVHD and that ROCK1/2 inhibition reduces the severity of aGVHD in mice by interfering with activation of multiple immune cell types.

Glioblastoma multiform (GBM) is a common and aggressive type of primary brain cancer that currently has no effective therapy. Here, the authors show, using a mouse GBM model and EGFRvIII-targeting chimeric antigen receptor (CAR)-T cells, that Intratumoral injection of interleukin-12 helps condition the microenvironment and promote anti-tumor immunity.

Genetic studies have connected polymorphisms in the IL-2 receptor alpha (IL2RA) gene with susceptibility to multiple sclerosis, but the mechanisms underlying this association are not clear. Here, the authors show that a polymorphism in IL2RA increases responsiveness to IL-2 and GM-CSF production in human T_Hcells.

Natural killer homeostasis is thought to be governed by gamma chain cytokines including IL-15. Here, the authors show that IL-12 can trigger the development of a distinct subset of natural killer cells with anti-tumour activity.

Becher and colleagues use a mouse model of multiple sclerosis to show that IFNγ is essential for the acquisition of a mature inflammatory phagocyte phenotype, while GM-CSF is required for phagocytosis and the production of IL-1β and ROS in Ly6C^hi monocytes during neuroinflammation.

In monozygotic twins discordant for multiple sclerosis, the influence of genetic predisposition and environmental factors is determined using matched-pair analyses.

IL-12 and IL-23 share the common p40 subunit yet have distinct immunological functions with IL-12 typically contributing to Th1 responses and IL-23 to Th17 responses. Here the authors show that current p40 based therapies for psoriasis are counterproductive owing to an IFN-γ-independent tissue protective function of IL-12 in skin.

Bacigaluppi and colleagues report that the accumulation of atypical mature and immature neutrophil subsets and a dysregulated emergency granulopoiesis response in aged mice and humans affect the outcome of stroke.

Combining the kinase inhibitor sorafenib with allogeneic stem cell transplantation boosts immune responses against a subtype of acute myelogenous leukemia, suggesting potential clinical benefit.

Among many populations of blood cells, high dimensional analysis using mass cytometry reveals classical monocyte frequency as strong predictors of response to PD-1 blockade therapy of melanoma.

Proinflammatory cytokine expression increases as a result of amyloid deposition in Alzheimer's disease. Frank L. Heppner and colleagues show that genetic and pharmacological inhibition of IL-12 and IL-23 signaling reduces plaque load and improves cognitive deficits in mouse models of Alzheimer's disease. As the concentration of p40 is also increased in the cerebrospinal fluid of individuals with Alzheimer's disease, this suggests that this pathway may be targeted therapeutically in patients.

Schneeberger, Kim, Geesdorf, Rajewsky, Heppner et al. tease IL-12 and IL-23 signaling apart in mouse models and human brain tissue to define a role for oligodendroglial and neuronal IL-12 signaling in neuroimmune crosstalk in Alzheimer’s disease.

It is now emerging that the neuroinflammation that is associated with Alzheimer disease may have a key role in driving this disease. In this Review, Heppner, Ransohoff and Becher examine the contribution of the immune system to the pathogenesis of this disorder.

The death of oligodendrocytes has been hypothesized to trigger the anti-myelin immunity observed in multiple sclerosis. In a mouse model, the authors show that diffuse oligodendrocyte death alone or in conjunction with immune activation does not initiate any anti-CNS immunity.

The T helper subset paradigm has been instrumental in informing our understanding of T cell diversity; however, modern single-cell analyses have revealed the limits of the concept. In their Perspective, Becher and colleagues propose an alternative framework in which to understand T helper diversity, based not on transcription factors and cytokines but rather physiological functionality.

Dimitriou et al. perform multiomic profiling of patients with melanoma experiencing immunotherapy-associated toxicity and identify a targetable role for type III-associated immune responses with an increase in CD4⁺ T cells expressing IL-17A.

With aging, the immune system undergoes severe changes that impact health in numerous ways. For a comprehensive, translational analysis of these alterations, Krishnarajah et al. here provide profiling of immune cell populations across 12 tissues from young and old mice.

A machine learning approach using high-dimensional phenotypic and functional profiling data identifies a multiple sclerosis-specific T cell population that is reduced following treatment.

Dormancy of disseminated cancer cells has been described in patients with breast cancer and associated with late metastatic relapses. Here the authors show that CD39⁺PD-1⁺CD8⁺ T cells correlate with increased disease free survival post-resection in breast cancer patients, and promote dormancy in a preclinical model.

In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.

Tumor-draining lymph nodes are often the first site of metastasis in breast cancer patients. Here, the authors show that metastatic lymph nodes are characterized by the accumulation of suppressive regulatory T cells with a distinct phenotype compared to matched non-invaded lymph nodes and tumors.

The detection of hypocretin-specific autoreactive CD4⁺ and CD8⁺ T cells in patients with narcolepsy reveals the autoimmune aetiology of this disorder.

Greter and colleagues identify a population of CD11c⁺F4/80⁺CD64⁺MHCII⁺CX3CR1⁺ macrophages in the mouse mammary gland that is induced by lactation and resembles several subsets of macrophages detected in human milk.

Single-cell transcriptomic profiling and functional assays are used to identify subpopulations of eosinophils that are present in the mouse gastrointestinal tract and provide insight into the role of these cells in inflammatory bowel diseases in humans.

A subpopulation of astrocytes characterized by the expression of LAMP1 and TRAIL limits inflammation in the central nervous system through a mechanism involving the microbiota-modulated expression of IFNγ in meningeal natural killer cells.

Dysregulated cytokine networks are important in the pathogenesis of neuroinflammation. This Review discusses targeting cytokines and their receptors in non-infectious central nervous system inflammatory diseases such as multiple sclerosis and neurosarcoidosis, as well as in the neurotoxic adverse events that can be triggered by cancer immunotherapy.

Single-cell RNA sequencing of cells from humans with multiple sclerosis and mice with a model of the disease identifies a population of disease-promoting astrocytes in which anti-oxidant and anti-inflammatory proteins are suppressed.

Modeling patient-individual resistance to immunotherapy is challenging. Here, the authors use a syngeneic experimental hypermutated orthotopic glioma model to define radiological and biological features that can predict or explain the mechanistic differences between responders and non-responders to immunotherapy.

Myeloid cells show great phenotypic and functional diversity. Newell and colleagues use mass cytometry with a panel of 38 mouse myeloid markers to describe myeloid cell phenotypic diversity in unprecedented depth within eight different tissues.