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Tumour dendritic cells (DCs) internalise antigen and upregulate CCR7, which directs their migration to tumour-draining lymph nodes (dLN). CCR7 expression is coupled to an activation programme enriched in regulatory molecule expression, including PD-L1. However, the spatio-temporal dynamics of CCR7 + DCs in anti-tumour immune responses remain unclear. Here, we use photoconvertible mice to precisely track DC migration. We report that CCR7 + DCs are the dominant DC population that migrate to the dLN, but a subset remains tumour-resident despite CCR7 expression. These tumour-retained CCR7 + DCs are phenotypically and transcriptionally distinct from their dLN counterparts and heterogeneous. Moreover, they progressively downregulate the expression of antigen presentation and pro-inflammatory transcripts with more prolonged tumour dwell-time. Tumour-residing CCR7 + DCs co-localise with PD-1 + CD8 + T cells in human and murine solid tumours, and following anti-PD-L1 treatment, upregulate stimulatory molecules including OX40L, thereby augmenting anti-tumour cytolytic activity. Altogether, these data uncover previously unappreciated heterogeneity in CCR7 + DCs that may underpin a variable capacity to support intratumoural cytotoxic T cells. Recognition of tumour antigen induces dendritic cell activation and migration to the lymph node. Here, the authors use photoconvertible mice to demonstrate that some activated dendritic cells are retained in tumours and gradually lose function, but their ability to support local anti-tumour responses can be augmented by anti-PD-L1 blockade.

Both traumatic and non‐traumatic spinal cord injuries (SCIs) can be categorized as damages done to our central nervous system (CNS). The patients' physical and mental health may suffer greatly because of traumatic SCI. With the widespread use of motor vehicles and increasingly aged population, the occurrence of SCI is more frequent than before, creating a considerable burden to global public health. The regeneration process of the spinal cord is hampered by a series of events that occur following SCI like edema, hemorrhage, formation of cystic cavities, and ischemia. An effective strategy for the treatment of SCI and functional recovery still has not been discovered; however, recent advances have been made in bioengineering fields that therapies based on cells, biomaterials, and biomolecules have proved effective in the repair of the spinal cord. In the light of worldwide importance of treatments for SCI, this article aims to provide a review of recent advances by first introducing the physiology, etiology, epidemiology, and mechanisms of SCI. We then put emphasis on the widely used clinical treatments and bioengineering strategies (cell‐based, biomaterial‐based, and biomolecule‐based) for the functional regeneration of the spinal cord as well as challenges faced by scientists currently. This article provides scientists and clinicians with a comprehensive outlook on the recent advances of preclinical and clinical treatments of SCI, hoping to help them find keys to the functional regeneration of SCI. Spinal cord injury is still an intricate accident for clinicians to handle. By reviewing recent advances on cell and tissue engineering, we aim to provide an insight into the most forefront neuroprotective and neuroregenerative strategies in order to predict where the field is going in the future. We hope that this review will help accelerate the clinical transformation of SCI regeneration strategies.

While antibody responses to neurovirulent pathogens are critical for clearance, the extent to which antibodies access the nervous system to ameliorate infection is poorly understood. In this study on herpes simplex virus 1 (HSV-1), we demonstrate that HSV-specific antibodies are present during HSV-1 latency in the nervous systems of both mice and humans. We show that antibody-secreting cells entered the trigeminal ganglion (TG), a key site of HSV infection, and persisted long after the establishment of latent infection. We also demonstrate the ability of passively administered IgG to enter the TG independently of infection, showing that the naive TG is accessible to antibodies. The translational implication of this finding is that human fetal neural tissue could contain HSV-specific maternally derived antibodies. Exploring this possibility, we observed HSV-specific IgG in HSV DNA-negative human fetal TG, suggesting passive transfer of maternal immunity into the prenatal nervous system. To further investigate the role of maternal antibodies in the neonatal nervous system, we established a murine model to demonstrate that maternal IgG can access and persist in neonatal TG. This maternal antibody not only prevented disseminated infection but also completely protected the neonate from neurological disease and death following HSV challenge. Maternal antibodies therefore have a potent protective role in the neonatal nervous system against HSV infection. These findings strongly support the concept that prevention of prenatal and neonatal neurotropic infections can be achieved through maternal immunization. IMPORTANCE Herpes simplex virus 1 is a common infection of the nervous system that causes devastating neonatal disease. Using mouse and human tissue, we discovered that antiviral antibodies accumulate in neural tissue after HSV-1 infection in adults. Similarly, these antibodies pass to the offspring during pregnancy. We found that antiviral maternal antibodies can readily access neural tissue of the fetus and neonate. These maternal antibodies then protect neonatal mice against HSV-1 neurological infection and death. These results underscore the previously unappreciated role of maternal antibodies in protecting fetal and newborn nervous systems against infection. These data suggest that maternal immunization would be efficacious at preventing fetal/neonatal neurological infections. Herpes simplex virus 1 is a common infection of the nervous system that causes devastating neonatal disease. Using mouse and human tissue, we discovered that antiviral antibodies accumulate in neural tissue after HSV-1 infection in adults. Similarly, these antibodies pass to the offspring during pregnancy. We found that antiviral maternal antibodies can readily access neural tissue of the fetus and neonate. These maternal antibodies then protect neonatal mice against HSV-1 neurological infection and death. These results underscore the previously unappreciated role of maternal antibodies in protecting fetal and newborn nervous systems against infection. These data suggest that maternal immunization would be efficacious at preventing fetal/neonatal neurological infections.

There is increasing interest in how immune cells in the meninges—the membranes that surround the brain and spinal cord—contribute to homeostasis and disease in the central nervous system 1 , 2 . The outer layer of the meninges, the dura mater, has recently been described to contain both innate and adaptive immune cells, and functions as a site for B cell development 3 , 4 , 5 – 6 . Here we identify organized lymphoid structures that protect fenestrated vasculature in the dura mater. The most elaborate of these dural-associated lymphoid tissues (DALT) surrounded the rostral-rhinal confluence of the sinuses and included lymphatic vessels. We termed this structure, which interfaces with the skull bone marrow and a comparable venous plexus at the skull base, the rostral-rhinal venolymphatic hub. Immune aggregates were present in DALT during homeostasis and expanded with age or after challenge with systemic or nasal antigens. DALT contain germinal centre B cells and support the generation of somatically mutated, antibody-producing cells in response to a nasal pathogen challenge. Inhibition of lymphocyte entry into the rostral-rhinal hub at the time of nasal viral challenge abrogated the generation of germinal centre B cells and class-switched plasma cells, as did perturbation of B–T cell interactions. These data demonstrate a lymphoid structure around vasculature in the dura mater that can sample antigens and rapidly support humoral immune responses after local pathogen challenge. Dural-associated lymphoid tissues are lymphoid structures around vascular hubs in the dura mater that sample antigens and rapidly support humoral immune responses after local pathogen challenge.

We investigated the role of inflammation in the pathogenesis of prodromal Parkinson's Disease (PD), performing single-cell RNAseq analysis of cerebrospinal fluid (CSF) and blood from 111 individuals, comparing control subjects with early prodromal PD and later PD to patients with multiple sclerosis (MS). Surprisingly, we identified a pleocytosis in the CSF, most pronounced in patients with early PD. Single-cell RNAseq revealed increases in CSF-specific microglia-like macrophages expressing JAK-STAT and TNFα signaling signatures in prodromal PD, with a lack of T cell activation in the CSF. The CSF macrophages exhibited similar transcriptional profiles to dural macrophages from human α-synuclein-expressing PD model mice. These findings uncover a myeloid-mediated TNFα inflammatory process in the CNS of patients with prodromal PD, suggesting a novel pathological mechanism in disease etiology.

C1q, the initiating protein of the classical complement cascade, mediates synapse loss in development and disease. In various mouse models of neurologic diseases, including Alzheimer's disease, C1q, which is secreted by microglia, the brain's resident macrophages, is found deposited on synapses in vulnerable brain regions. However, what underlies C1q deposition on synapses in the adult brain is unclear. Using in vivo chemogenetics, we demonstrate that neuronal hyperactivity acts as a trigger for region-specific deposition of C1q, which is required for activity-dependent synapse loss. Further, using spatial transcriptomics, live cell tracking, super-resolution microscopy and other molecular and cellular tools, we report a role for B lymphocyte lineage cells and immunoglobulins in the activity-dependent C1q deposition and synapse loss. Overall, our work suggests a link between neuronal hyperactivity and C1q-mediated synapse loss in the adult brain and introduces immunoglobulins as players in this process.Competing Interest StatementThe authors have declared no competing interest.

Climate change and justice are so closely associated that many people take it for granted that a global climate treaty should--indeed, must--directly address both issues together. But, in fact, this would be a serious mistake, one that, by dooming effective international limits on greenhouse gases, would actually make the world's poor and developing nations far worse off. This is the provocative and original argument ofClimate Change Justice. Eric Posner and David Weisbach strongly favor both a climate change agreement and efforts to improve economic justice. But they make a powerful case that the best--and possibly only--way to get an effective climate treaty is to exclude measures designed to redistribute wealth or address historical wrongs against underdeveloped countries. In clear language,Climate Change Justiceproposes four basic principles for designing the only kind of climate treaty that will work--a forward-looking agreement that requires every country to make greenhouse--gas reductions but still makes every country better off in its own view. This kind of treaty has the best chance of actually controlling climate change and improving the welfare of people around the world.

Tumour dendritic cells (DCs) internalise antigen and upregulate CCR7, which directs their migration to tumour-draining lymph nodes (dLN). CCR7 expression is coupled to a maturation programme enriched in regulatory molecule expression, including PD-L1, termed mRegDC. However, the spatio- temporal dynamics and role of mRegDCs in anti-tumour immune responses remain unclear. Using photoconvertible mice to precisely track DC migration, we found that mRegDCs were the dominant DC population arriving in the dLN, but a subset remained tumour-resident despite CCR7 expression. These tumour-retained mRegDCs were phenotypically and transcriptionally distinct from their dLN counterparts and were heterogeneous. Specifically, they demonstrated a progressive reduction in the expression of antigen presentation and pro-inflammatory transcripts with more prolonged tumour dwell-time. Tumour mRegDCs spatially co-localised with PD-1+CD8+ T cells in human and murine solid tumours. Following anti-PD-L1 treatment, tumour-residing mRegDCs adopted a state enriched in lymphocyte stimulatory molecules, including OX40L, which was capable of augmenting anti- tumour cytolytic activity. Altogether, these data uncover previously unappreciated heterogeneity in mRegDCs that may underpin a variable capacity to support intratumoural cytotoxic T cells, and provide insights into their role in cancer immunotherapy.