Stem-like T cells in cancer and autoimmunity.

Stem-like T cells are characterized by their ability to self-renew, survive long-term, and give rise to a heterogeneous pool of effector and memory T cells. Recent advances in single-cell RNA-sequencing (scRNA-seq) and lineage tracing technologies revealed an important role for stem-like T cells in both autoimmunity and cancer. In cancer, stem-like T cells constitute an important arm of the anti-tumor immune response by giving rise to effector T cells that mediate tumor control. In contrast, in autoimmunity stem-like T cells perform an unfavorable role by forming a reservoir of long-lived autoreactive cells that replenish the pathogenic, effector T-cell pool and thereby driving disease pathology. This review provides background on the discovery of stem-like T cells and their function in cancer and autoimmunity. Moreover, the influence of the microbiota and metabolism on the stem-like T-cell pool is summarized. Lastly, the implications of our knowledge about stem-like T cells for clinical treatment strategies for cancer and autoimmunity will be discussed.

Deciphering cell states and genealogies of human haematopoiesis.

The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived haematopoietic stem cells (HSCs)1. Perturbations to this process underlie diverse diseases, but the clonal contributions to human haematopoiesis and how this changes with age remain incompletely understood. Although recent insights have emerged from barcoding studies in model systems2-5, simultaneous detection of cell states and phylogenies from natural barcodes in humans remains challenging. Here we introduce an improved, single-cell lineage-tracing system based on deep detection of naturally occurring mitochondrial DNA mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs and map the physiological state and output of clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as both differences in total HSC output and biases towards the production of different mature cell types. We also find that the diversity of HSC clones decreases markedly with age, leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides a clonally resolved and cell-state-aware atlas of human haematopoiesis at single-cell resolution, showing an unappreciated functional diversity of human HSC clones and, more broadly, paving the way for refined studies of clonal dynamics across a range of tissues in human health and disease.

Beyond the Tricks: The Science and Comparative Cognition of Magic.

Magic is an art form that has fascinated humans for centuries. Recently, the techniques used by magicians to make their audience experience the impossible have attracted the attention of psychologists, who, in just a couple of decades, have produced a large amount of research regarding how these effects operate, focusing on the blind spots in perception and roadblocks in cognition that magic techniques exploit. Most recently, this investigation has given a pathway to a new line of research that uses magic effects to explore the cognitive abilities of nonhuman animals. This new branch of the scientific study of magic has already yielded new evidence illustrating the power of magic effects as a psychological tool for nonhuman animals. This review aims to give a thorough overview of the research on both the human and nonhuman perception of magic effects by critically illustrating the most prominent works of both fields of inquiry.

Octopus toss-up: Is debris throwing driven by intent?

In a noteworthy observation, Godfrey-Smith and colleagues report the first evidence of debris throwing in wild octopuses, including instances where they target conspecifics. Proposing parallels with behaviours observed in select social mammals, this discovery prompts inquiries into the extent of their similarity and the potential role of cognition.

Cephalopod learning and memory.

Cephalopod molluscs are renowned for their unique central nervous system - a donut-shaped brain organised around the oesophagus. This brain supports sophisticated learning and memory abilities. Between the 1950s and 1980s, these cognitive abilities were extensively studied in octopus (Figure 1A) - a now leading model for the study of memory and its neural substrates (approximately 200 papers during this period). The focus on octopus learning and memory was mainly due to their curious nature and the fact that they adapt to laboratory-controlled conditions, making them easy to test and maintain in captivity. Research on cephalopod cognition began to widen in the late 20th century, when scientists started focusing on other coleoid cephalopods (i.e., cuttlefish and squid) (Figure 1B,C), and not just on associative learning and memory per se, but other more complex aspects of cognition such as episodic-like memory (the ability to remember the what, where, and when of a past event), source memory (the retrieval of contextual details from a memory), and self-control (the ability to inhibit an action in the present to gain a more valuable future reward). Attention broadened further over the last two decades to focus on the shelled cephalopods - the nautiloids (Figure 1D). The nautiloids have relatively primitive brains compared to their soft-bodied cousins (octopus, cuttlefish, and squid) but research shows that they are still able to comparatively succeed in some cognitive tasks. In this primer, we will provide a general description of the types of memory studied in cephalopods, and discuss learning and memory experiments that address the main challenges cephalopods face during their daily lives: navigation, timing, and food selection. Determining the type of information cephalopods learn and remember and whether they use such information to overcome ecological challenges will highlight why these invertebrates evolved large and sophisticated brains.

Targeting PGLYRP1 promotes antitumor immunity while inhibiting autoimmune neuroinflammation.

Co-inhibitory and checkpoint molecules suppress T cell function in the tumor microenvironment, thereby rendering T cells dysfunctional. Although immune checkpoint blockade is a successful treatment option for multiple human cancers, severe autoimmune-like adverse effects can limit its application. Here, we show that the gene encoding peptidoglycan recognition protein 1 (PGLYRP1) is highly coexpressed with genes encoding co-inhibitory molecules, indicating that it might be a promising target for cancer immunotherapy. Genetic deletion of Pglyrp1 in mice led to decreased tumor growth and an increased activation/effector phenotype in CD8+ T cells, suggesting an inhibitory function of PGLYRP1 in CD8+ T cells. Surprisingly, genetic deletion of Pglyrp1 protected against the development of experimental autoimmune encephalomyelitis, a model of autoimmune disease in the central nervous system. PGLYRP1-deficient myeloid cells had a defect in antigen presentation and T cell activation, indicating that PGLYRP1 might function as a proinflammatory molecule in myeloid cells during autoimmunity. These results highlight PGLYRP1 as a promising target for immunotherapy that, when targeted, elicits a potent antitumor immune response while protecting against some forms of tissue inflammation and autoimmunity.

The Inner Lives of Cephalopods.

The minds of cephalopods have captivated scientists for millennia, yet the extent that we can understand their subjective experiences remains contested. In this article, we consider the sum of our scientific progress towards understanding the inner lives of cephalopods. Here, we outline the behavioral responses to specific experimental paradigms that are helping us to reveal their subjective experiences. We consider evidence from three broad research categories, which help to illuminate whether soft-bodied cephalopods (octopus, cuttlefish, and squid) have an awareness of self, awareness of others, and an awareness of time. Where there are current gaps in the literature, we outline cephalopod behaviors that warrant experimental investigation. We argue that investigations, especially framed through the lens of comparative psychology, have the potential to extend our understanding of the inner lives of this extraordinary class of animals.

B-cell-specific checkpoint molecules that regulate anti-tumour immunity.

The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth1,2. Here, using high-throughput flow cytometry as well as bulk and single-cell RNA-sequencing and B-cell-receptor-sequencing analysis of B cells temporally during B16F10 melanoma growth, we identified a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice. The expanding B cell subset expresses the cell surface molecule T cell immunoglobulin and mucin domain 1 (TIM-1, encoded by Havcr1) and a unique transcriptional signature, including multiple co-inhibitory molecules such as PD-1, TIM-3, TIGIT and LAG-3. Although conditional deletion of these co-inhibitory molecules on B cells had little or no effect on tumour burden, selective deletion of Havcr1 in B cells both substantially inhibited tumour growth and enhanced effector T cell responses. Loss of TIM-1 enhanced the type 1 interferon response in B cells, which augmented B cell activation and increased antigen presentation and co-stimulation, resulting in increased expansion of tumour-specific effector T cells. Our results demonstrate that manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.

Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut.

Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.

TH17 cell heterogeneity and its role in tissue inflammation.

Since their discovery almost two decades ago, interleukin-17-producing CD4+ T cells (TH17 cells) have been implicated in the pathogenesis of multiple autoimmune and inflammatory disorders. In addition, TH17 cells have been found to play an important role in tissue homeostasis, especially in the intestinal mucosa. Recently, the use of single-cell technologies, along with fate mapping and various mutant mouse models, has led to substantial progress in the understanding of TH17 cell heterogeneity in tissues and of TH17 cell plasticity leading to alternative T cell states and differing functions. In this Review, we discuss the heterogeneity of TH17 cells and the role of this heterogeneity in diverse functions of TH17 cells from homeostasis to tissue inflammation. In addition, we discuss TH17 cell plasticity and its incorporation into the current understanding of T cell subsets and alternative views on the role of TH17 cells in autoimmune and inflammatory diseases.

Waiting for a better possibility: delay of gratification in corvids and its relationship to other cognitive capacities.

Self-control, the ability to resist temptation and wait for better but delayed possibilities, is an important cognitive skill that underpins decision-making and planning. The capacity to exert self-control has been linked to intelligence in humans, chimpanzees and most recently cuttlefish. Here, we presented 10 Eurasian jays, Garrulus glandarius, with a delayed maintenance task, which measured the ability to choose a preferred outcome as well as the ability to sustain the delay prior to that outcome. Jays were able to wait for better possibilities, but maximum wait times varied across the subjects. We also presented them with five cognitive tasks that assessed spatial memory, spatial relationships and learning capacity. These tasks are commonly used as measures of general intelligence within an ecological context. Individual performance was correlated across the cognitive tasks, which suggests that there was a general intelligence factor underlying their performance. Performance in these tasks was correlated significantly with the jays' capacity to wait for better possibilities. This study demonstrates that self-control and intelligence are correlated in jays. The fact that this correlation exists in diverse species suggests that self-control is a fundamental feature of cognition. Our results are discussed in the context of convergent evolution. This article is part of the theme issue 'Thinking about possibilities: mechanisms, ontogeny, functions and phylogeny'.

Induction of a colitogenic phenotype in Th1-like cells depends on interleukin-23 receptor signaling.

Interleukin-23 receptor plays a critical role in inducing inflammation and autoimmunity. Here, we report that Th1-like cells differentiated in vitro with IL-12 + IL-21 showed similar IL-23R expression to that of pathogenic Th17 cells using eGFP reporter mice. Fate mapping established that these cells did not transition through a Th17 cell state prior to becoming Th1-like cells, and we observed their emergence in vivo in the T cell adoptive transfer colitis model. Using IL-23R-deficient Th1-like cells, we demonstrated that IL-23R was required for the development of a highly colitogenic phenotype. Single-cell RNA sequencing analysis of intestinal T cells identified IL-23R-dependent genes in Th1-like cells that differed from those expressed in Th17 cells. The perturbation of one of these regulators (CD160) in Th1-like cells inhibited the induction of colitis. We thus uncouple IL-23R as a purely Th17 cell-specific factor and implicate IL-23R signaling as a pathogenic driver in Th1-like cells inducing tissue inflammation.

Antigen presentation safeguards the integrity of the hematopoietic stem cell pool.

Hematopoietic stem and progenitor cells (HSPCs) are responsible for the production of blood and immune cells. Throughout life, HSPCs acquire oncogenic aberrations that can cause hematological cancers. Although molecular programs maintaining stem cell integrity have been identified, safety mechanisms eliminating malignant HSPCs from the stem cell pool remain poorly characterized. Here, we show that HSPCs constitutively present antigens via major histocompatibility complex class II. The presentation of immunogenic antigens, as occurring during malignant transformation, triggers bidirectional interactions between HSPCs and antigen-specific CD4+ T cells, causing stem cell proliferation, differentiation, and specific exhaustion of aberrant HSPCs. This immunosurveillance mechanism effectively eliminates transformed HSPCs from the hematopoietic system, thereby preventing leukemia onset. Together, our data reveal a bidirectional interaction between HSPCs and CD4+ T cells, demonstrating that HSPCs are not only passive receivers of immunological signals but also actively engage in adaptive immune responses to safeguard the integrity of the stem cell pool.

Disruption of the IL-33-ST2-AKT signaling axis impairs neurodevelopment by inhibiting microglial metabolic adaptation and phagocytic function.

To accommodate the changing needs of the developing brain, microglia must undergo substantial morphological, phenotypic, and functional reprogramming. Here, we examined whether cellular metabolism regulates microglial function during neurodevelopment. Microglial mitochondria bioenergetics correlated with and were functionally coupled to phagocytic activity in the developing brain. Transcriptional profiling of microglia with diverse metabolic profiles revealed an activation signature wherein the interleukin (IL)-33 signaling axis is associated with phagocytic activity. Genetic perturbation of IL-33 or its receptor ST2 led to microglial dystrophy, impaired synaptic function, and behavioral abnormalities. Conditional deletion of Il33 from astrocytes or Il1rl1, encoding ST2, in microglia increased susceptibility to seizures. Mechanistically, IL-33 promoted mitochondrial activity and phagocytosis in an AKT-dependent manner. Mitochondrial metabolism and AKT activity were temporally regulated in vivo. Thus, a microglia-astrocyte circuit mediated by the IL-33-ST2-AKT signaling axis supports microglial metabolic adaptation and phagocytic function during early development, with implications for neurodevelopmental and neuropsychiatric disorders.

Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity.

While intestinal Th17 cells are critical for maintaining tissue homeostasis, recent studies have implicated their roles in the development of extra-intestinal autoimmune diseases including multiple sclerosis. However, the mechanisms by which tissue Th17 cells mediate these dichotomous functions remain unknown. Here, we characterized the heterogeneity, plasticity, and migratory phenotypes of tissue Th17 cells in vivo by combined fate mapping with profiling of the transcriptomes and TCR clonotypes of over 84,000 Th17 cells at homeostasis and during CNS autoimmune inflammation. Inter- and intra-organ single-cell analyses revealed a homeostatic, stem-like TCF1+ IL-17+ SLAMF6+ population that traffics to the intestine where it is maintained by the microbiota, providing a ready reservoir for the IL-23-driven generation of encephalitogenic GM-CSF+ IFN-γ+ CXCR6+ T cells. Our study defines a direct in vivo relationship between IL-17+ non-pathogenic and GM-CSF+ and IFN-γ+ pathogenic Th17 populations and provides a mechanism by which homeostatic intestinal Th17 cells direct extra-intestinal autoimmune disease.

Jays are sensitive to cognitive illusions.

Jays hide food caches, steal them from conspecifics and use tactics to minimize cache theft. Jays are sensitive to the content of their own caches, retrieving items depending on their preferences and the perishability of the cached item. Whether jays impose the same content sensitivity when they steal caches is less clear. We adapted the 'cups-and-balls' magic routine, creating a cognitive illusion to test whether jays are sensitive to the (i) content of hidden items and (ii) type of displacement. Subjects were presented with two conditions in which hidden food was consistent with their expectations; and two conditions in which food was manipulated to violate their expectations by switching their second preferred food for their preferred food (up-value) or vice versa (de-value). Subjects readily accepted food when it was consistent with their expectations but were more likely to re-inspect the baited cup and alternative cup when their expectations were violated. In the de-value condition, jays exhibited longer latencies to consume the food and often rejected it. Dominant subjects were more likely to reject the food, suggesting that social factors influence their responses to cognitive illusions. Using cognitive illusions offers innovative avenues for investigating the psychological constraints in diverse animal minds.

Episodic-like memory is preserved with age in cuttlefish.

Episodic memory, remembering past experiences based on unique what-where-when components, declines during ageing in humans, as does episodic-like memory in non-human mammals. By contrast, semantic memory, remembering learnt knowledge without recalling unique what-where-when features, remains relatively intact with advancing age. The age-related decline in episodic memory likely stems from the deteriorating function of the hippocampus in the brain. Whether episodic memory can deteriorate with age in species that lack a hippocampus is unknown. Cuttlefish are molluscs that lack a hippocampus. We test both semantic-like and episodic-like memory in sub-adults and aged-adults nearing senescence (n = 6 per cohort). In the semantic-like memory task, cuttlefish had to learn that the location of a food resource was dependent on the time of day. Performance, measured as proportion of correct trials, was comparable across age groups. In the episodic-like memory task, cuttlefish had to solve a foraging task by retrieving what-where-when information about a past event with unique spatio-temporal features. In this task, performance was comparable across age groups; however, aged-adults reached the success criterion (8/10 correct choices in consecutive trials) significantly faster than sub-adults. Contrary to other animals, episodic-like memory is preserved in aged cuttlefish, suggesting that memory deterioration is delayed in this species.

Metabolic modeling of single Th17 cells reveals regulators of autoimmunity.

Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays. Compass also predicted that Th17 pathogenicity was associated with arginine and downstream polyamine metabolism. Indeed, polyamine-related enzyme expression was enhanced in pathogenic Th17 and suppressed in Treg cells. Chemical and genetic perturbation of polyamine metabolism inhibited Th17 cytokines, promoted Foxp3 expression, and remodeled the transcriptome and epigenome of Th17 cells toward a Treg-like state. In vivo perturbations of the polyamine pathway altered the phenotype of encephalitogenic T cells and attenuated tissue inflammation in CNS autoimmunity.

Exploring the perceptual inabilities of Eurasian jays (Garrulus glandarius) using magic effects.

In recent years, scientists have begun to use magic effects to investigate the blind spots in our attention and perception [G. Kuhn, Experiencing the Impossible: The Science of Magic (2019); S. Macknik, S. Martinez-Conde, S. Blakeslee, Sleights of Mind: What the Neuroscience of Magic Reveals about Our Everyday Deceptions (2010)]. Recently, we suggested that similar techniques could be transferred to nonhuman animal observers and that such an endeavor would provide insight into the inherent commonalities and discrepancies in attention and perception in human and nonhuman animals [E. Garcia-Pelegrin, A. K. Schnell, C. Wilkins, N. S. Clayton, Science 369, 1424-1426 (2020)]. Here, we performed three different magic effects (palming, French drop, and fast pass) to a sample of six Eurasian jays (Garrulus glandarius). These magic effects were specifically chosen as they utilize different cues and expectations that mislead the spectator into thinking one object has or has not been transferred from one hand to the other. Results from palming and French drop experiments suggest that Eurasian jays have different expectations from humans when observing some of these effects. Specifically, Eurasian jays were not deceived by effects that required them to expect an object to move between hands when observing human hand manipulations. However, similar to humans, Eurasian jays were misled by magic effects that utilize fast movements as a deceptive action. This study investigates how another taxon perceives the magician's techniques of deception that commonly deceive humans.