The ß1-adrenergic receptor links sympathetic nerves to T cell exhaustion.

CD8+ T cells are essential components of the immune response against viral infections and tumours, and are capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, T cells enter a state known as exhaustion1. Although it is clear that chronic antigen contributes to CD8+ T cell exhaustion, less is known about how stress responses in tissues regulate T cell function. Here we show a new link between the stress-associated catecholamines and the progression of T cell exhaustion through the ß1-adrenergic receptor ADRB1. We identify that exhausted CD8+ T cells increase ADRB1 expression and that exposure of ADRB1+ T cells to catecholamines suppresses their cytokine production and proliferation. Exhausted CD8+ T cells cluster around sympathetic nerves in an ADRB1-dependent manner. Ablation of ß1-adrenergic signalling limits the progression of T cells towards the exhausted state in chronic infection and improves effector functions when combined with immune checkpoint blockade (ICB) in melanoma. In a pancreatic cancer model resistant to ICB, ß-blockers and ICB synergize to boost CD8+ T cell responses and induce the development of tissue-resident memory-like T cells. Malignant disease is associated with increased catecholamine levels in patients2,3, and our results establish a connection between the sympathetic stress response, tissue innervation and T cell exhaustion. Here, we uncover a new mechanism by which blocking ß-adrenergic signalling in CD8+ T cells rejuvenates anti-tumour functions.

Caspase-7 activates ASM to repair gasdermin and perforin pores.

Among the caspases that cause regulated cell death, a unique function for caspase-7 has remained elusive. Caspase-3 performs apoptosis, whereas caspase-7 is typically considered an inefficient back-up. Caspase-1 activates gasdermin D pores to lyse the cell; however, caspase-1 also activates caspase-7 for unknown reasons1. Caspases can also trigger cell-type-specific death responses; for example, caspase-1 causes the extrusion of intestinal epithelial cell (IECs) in response to infection with Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium)2,3. Here we show in both organoids and mice that caspase-7-deficient IECs do not complete extrusion. Mechanistically, caspase-7 counteracts gasdermin D pores and preserves cell integrity by cleaving and activating acid sphingomyelinase (ASM), which thereby generates copious amounts of ceramide to enable enhanced membrane repair. This provides time to complete the process of IEC extrusion. In parallel, we also show that caspase-7 and ASM cleavage are required to clear Chromobacterium violaceum and Listeria monocytogenes after perforin-pore-mediated attack by natural killer cells or cytotoxic T lymphocytes, which normally causes apoptosis in infected hepatocytes. Therefore, caspase-7 is not a conventional executioner but instead is a death facilitator that delays pore-driven lysis so that more-specialized processes, such as extrusion or apoptosis, can be completed before cell death. Cells must put their affairs in order before they die.

Inflammasomes Coordinate Pyroptosis and Natural Killer Cell Cytotoxicity to Clear Infection by a Ubiquitous Environmental Bacterium.

Defective neutrophils in patients with chronic granulomatous disease (CGD) cause susceptibility to extracellular and intracellular infections. Microbes must first be ejected from intracellular niches to expose them to neutrophil attack, so we hypothesized that inflammasomes detect certain CGD pathogens upstream of neutrophil killing. Here, we identified one such ubiquitous environmental bacterium, Chromobacterium violaceum, whose extreme virulence was fully counteracted by the NLRC4 inflammasome. Caspase-1 protected via two parallel pathways that eliminated intracellular replication niches. Pyroptosis was the primary bacterial clearance mechanism in the spleen, but both pyroptosis and interleukin-18 (IL-18)-driven natural killer (NK) cell responses were required for liver defense. NK cells cleared hepatocyte replication niches via perforin-dependent cytotoxicity, whereas interferon-γ was not required. These insights suggested a therapeutic approach: exogenous IL-18 restored perforin-dependent cytotoxicity during infection by the inflammasome-evasive bacterium Listeria monocytogenes. Therefore, inflammasomes can trigger complementary programmed cell death mechanisms, directing sterilizing immunity against intracellular bacterial pathogens.

Reassessing the Evolutionary Importance of Inflammasomes.

Inflammasomes monitor the cytosol for microbial contamination or perturbation and, thus, are predicted to provide potent defense against infection. However, the compendium of data from murine infection models suggests that inflammasomes merely delay the course of disease, allowing the host time to mount an adaptive response. Interpretations of such results are confounded by inflammasome-evasion strategies of vertebrate-adapted pathogens. Conversely, environmental opportunistic pathogens have not evolved in the context of inflammasomes and, therefore, are less likely to evade them. Indeed, opportunistic pathogens do not normally cause disease in wild-type animals. Accordantly, the extreme virulence of two opportunistic bacterial pathogens, Burkholderia thailandensis and Chromobacterium violaceum, is fully counteracted by inflammasomes in murine models. This leads us to propose a new hypothesis: perhaps animals maintain inflammasomes over evolutionary time not to defend against vertebrate-adapted pathogens but instead to counteract infection by a plethora of undiscovered opportunistic pathogens residing in the environment.

NAIP inflammasomes give the NOD to bacterial ligands.

NLRs are innate immune sensors that monitor the sanctity of the cytosolic compartment. In a recent paper in Molecular Cell, Tenthorey et al. reveal a novel ligand-sensing interface within regions of the oligomerization domain of the NAIPs, rather than within the leucine-rich repeats, as was anticipated.

A phenotype at last: essential role for the Yersinia enterocolitica Ysa type III secretion system in a Drosophila melanogaster S2 cell model.

The highly pathogenic Yersinia enterocolitica strains have a chromosomally encoded type III secretion system (T3SS) that is expressed and functional in vitro only when the bacteria are cultured at 26 °C. Mutations that render this system nonfunctional are slightly attenuated in the mouse model of infection only following an oral inoculation and only at early time points postinfection. The discrepancy between the temperature required for the Ysa gene expression and the physiological temperature required for mammalian model systems has made defining the role of this T3SS challenging. Therefore, we explored the use of Drosophila S2 cells as a model system for studying Ysa function. We show here that Y. enterocolitica is capable of infecting S2 cells and replicating intracellularly to high levels, an unusual feature of this pathogen. Importantly, we show that the Ysa T3SS is required for robust intracellular replication. A secretion-deficient mutant lacking the secretin gene, ysaC, is defective in replication within S2 cells, marking the first demonstration of a pronounced Ysa-dependent virulence phenotype. Establishment of S2 cells as a model for Y. enterocolitica infection provides a versatile tool to elucidate the role of the Ysa T3SS in the life cycle of this gastrointestinal pathogen.

An innate granuloma eradicates an environmental pathogen using Gsdmd and Nos2.

Granulomas often form around pathogens that cause chronic infections. Here, we discover an innate granuloma model in mice with an environmental bacterium called Chromobacterium violaceum. Granuloma formation not only successfully walls off, but also clears, the infection. The infected lesion can arise from a single bacterium that replicates despite the presence of a neutrophil swarm. Bacterial replication ceases when macrophages organize around the infection and form a granuloma. This granuloma response is accomplished independently of adaptive immunity that is typically required to organize granulomas. The C. violaceum-induced granuloma requires at least two separate defense pathways, gasdermin D and iNOS, to maintain the integrity of the granuloma architecture. This innate granuloma successfully eradicates C. violaceum infection. Therefore, this C. violaceum-induced granuloma model demonstrates that innate immune cells successfully organize a granuloma and thereby resolve infection by an environmental pathogen.

An innate granuloma eradicates an environmental pathogen using Gsdmd and Nos2.

Granulomas often form around pathogens that cause chronic infections. Here, we discover a novel granuloma model in mice. Chromobacterium violaceum is an environmental bacterium that stimulates granuloma formation that not only successfully walls off but also clears the infection. The infected lesion can arise from a single bacterium that replicates in the presence of a neutrophil swarm. Bacterial replication ceases when macrophages organize around the infection and form a granuloma. This granuloma response is accomplished independently of adaptive immunity that is typically required to organize granulomas. The C. violaceum -induced granuloma requires at least two separate defense pathways, gasdermin D and iNOS, to maintain the integrity of the granuloma architecture. These innate granulomas successfully eradicate C. violaceum infection. Therefore, this new C. violaceum -induced granuloma model demonstrates that innate immune cells successfully organize a granuloma and thereby eradicate infection by an environmental pathogen.

Supporting the Next Generation of Scientists to Lead Cancer Immunology Research.

Recent success in the use of immunotherapy for a broad range of cancers has propelled the field of cancer immunology to the forefront of cancer research. As more and more young investigators join the community of cancer immunologists, the Arthur L. Irving Family Foundation Cancer Immunology Symposium provided a platform to bring this expanding and vibrant community together and support the development of the future leaders in the field. This commentary outlines the lessons that emerged from the inaugural symposium highlighting the areas of scientific and career development that are essential for professional growth in the field of cancer immunology and beyond. Leading scientists and clinicians in the field provided their experience on the topics of scientific trajectory, career trajectory, publishing, fundraising, leadership, mentoring, and collaboration. Herein, we provide a conceptual and practical framework for career development to the broader scientific community.

Neutrophil Caspase-11 Is Essential to Defend against a Cytosol-Invasive Bacterium.

Either caspase-1 or caspase-11 can cleave gasdermin D to cause pyroptosis, eliminating intracellular replication niches. We previously showed that macrophages detect Burkholderia thailandensis via NLRC4, triggering the release of interleukin (IL)-18 and driving an essential interferon (IFN)-γ response that primes caspase-11. We now identify the IFN-γ-producing cells as a mixture of natural killer (NK) and T cells. Although both caspase-1 and caspase-11 can cleave gasdermin D in macrophages and neutrophils, we find that NLRC4-activated caspase-1 triggers pyroptosis in macrophages, but this pathway does not trigger pyroptosis in neutrophils. In contrast, caspase-11 triggers pyroptosis in both macrophages and neutrophils. This translates to an absolute requirement for caspase-11 in neutrophils during B. thailandensis infection in mice. We present an example of inflammasome sensors causing diverging outcomes in different cell types. Thus, cell fates are dictated not simply by the pathogen or inflammasome, but also by how the cell is wired to respond to detection events.