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T cells undergo extensive chromatin remodeling over several days following stimulation through the T cell receptor. However, the kinetics and gene loci targeted by early remodeling events within the first 24 hours of T cell priming to orchestrate effector differentiation have not been well described. We identified that chromatin accessibility is rapidly and extensively remodeled within 1 hour of stimulation of naïve CD8+ T cells, leading to increased global chromatin accessibility at many effector T cell-associated genes that are enriched for AP-1, early growth response (EGR), and nuclear factor of activated T cells (NFAT) binding sites, but this short duration of stimulation is insufficient for commitment to clonal expansion in vivo. Sustained 24-hour stimulation led to further chromatin remodeling and was sufficient to enable clonal expansion. These data suggest that the duration of antigen receptor signaling is intimately coupled to chromatin remodeling and activation of genes involved in effector cell differentiation and highlight a potential mechanism that helps CD8+ T cells discriminate between foreign- and self-antigens.

CD8+ T cells provide host protection against pathogens by differentiating into distinct effector and memory cell subsets, but how chromatin is site-specifically remodeled during their differentiation is unclear. Due to its critical role in regulating chromatin and enhancer accessibility through its nucleosome remodeling activities, we investigated the role of the canonical BAF (cBAF) chromatin remodeling complex in antiviral CD8+ T cells during infection. ARID1A, a subunit of cBAF, was recruited early after activation and established de novo open chromatin regions (OCRs) at enhancers. Arid1a deficiency impaired the opening of thousands of activation-induced enhancers, leading to loss of TF binding, dysregulated proliferation and gene expression, and failure to undergo terminal effector differentiation. Although Arid1a was dispensable for circulating memory cell formation, tissue-resident memory (Trm) formation was strongly impaired. Thus, cBAF governs the enhancer landscape of activated CD8+ T cells that orchestrates TF recruitment and activity and the acquisition of specific effector and memory differentiation states.

This study examines the impact of school (*) librarian full-time equivalent (FTE) levels on student achievement in Missouri using state-level assessment data. The researchers obtained publicly available, aggregated data directly from the Missouri Department of Elementary and Secondary Education (MO DESE) to conduct statistical analyses on multiple districts, years, and content areas. The dataset included data points from Missouri K-12 public schools over a nine-year period. The analysis utilized ANOVA and post-hoc tests to compare proficiency rates across FTE levels (no librarian, part-time librarian, and full-time librarian) for each school level and content area. Results indicated that schools with full-time librarians had significantly higher proficiency rates compared to schools with part-time or no librarians. Furthermore, the effect sizes demonstrated the positive impact of having a school librarian on student achievement across school levels and content areas. This study provides evidence supporting the importance of school librarians in enhancing student performance on state-level assessments., Introduction For over 50 years, research that demonstrates school librarians have a positive impact on student achievement has been published. Nearly 60 different studies in 22 states have found statistically [...]

Background Successful containment strategies for SARS-CoV-2, the causative virus of the COVID-19 pandemic, have involved widespread population testing that identifies infections early and enables rapid contact tracing. In this study, we developed a rapid and inexpensive RT- qPCR testing pipeline for population-level SARS-CoV-2 detection, and used this pipeline to establish a clinical laboratory dedicated to COVID-19 testing at the University of California San Diego (UCSD) with a processing capacity of 6,000 samples per day and next-day result turnaround times. Methods and findings Using this pipeline, we screened 6,786 healthcare workers and first responders, and 21,220 students, faculty, and staff from UCSD. Additionally, we screened 6,031 preschool-grade 12 students and staff from public and private schools across San Diego County that remained fully or partially open for in-person teaching during the pandemic. Between April 17, 2020 and February 5, 2021, participants provided 161,582 nasal swabs that were tested for the presence of SARS-CoV-2. Overall, 752 positive tests were obtained, yielding a test positivity rate of 0.47%. While the presence of symptoms was significantly correlated with higher viral load, most of the COVID-19 positive participants who participated in symptom surveys were asymptomatic at the time of testing. The positivity rate among preschool-grade 12 schools that remained open for in-person teaching was similar to the positivity rate at UCSD and lower than that of San Diego County, with the children in private schools being less likely to test positive than the adults at these schools. Conclusions Most schools across the United States have been closed for in-person learning for much of the 2020-2021 school year, and their safe reopening is a national priority. However, as there are no vaccines against SARS-CoV-2 currently available to the majority of school-aged children, the traditional strategies of mandatory masking, physical distancing, and repeated viral testing of students and staff remain key components of risk mitigation in these settings. The data presented here suggest that the safety measures and repeated testing actions taken by participating healthcare and educational facilities were effective in preventing outbreaks, and that a similar combination of risk-mitigation strategies and repeated testing may be successfully adopted by other healthcare and educational systems.

Tissue-resident memory CD8+ T cells (Trm) provide host protection through continuous surveillance of non-lymphoid tissues. Using single-cell RNA-sequencing (scRNA-seq) and genetic reporter mice, we identified discrete lineages of intestinal antigen-specific CD8+ T cells, including a Blimp1hiId3lo tissue-resident effector cell population most prominent in the early phase of acute viral and bacterial infections and a molecularly distinct Blimp1loId3hi tissue-resident memory population that subsequently accumulated at later infection time points. These Trm populations exhibited distinct cytokine production, secondary memory potential, and transcriptional programs including differential roles for transcriptional regulators Blimp1, T-bet, Id2, and Id3 in supporting and maintaining intestinal Trm. Extending our analysis to malignant tissue, we also identified discrete populations of effector-like and memory-like CD8+ T cell populations with tissue-resident gene-expression signatures that shared features of terminally exhausted and progenitor-exhausted T cells, respectively. Our findings provide insight into the development and functional heterogeneity of Trm cells, which has implications for enhancing vaccination and immunotherapy approaches.

Conventional antiviral memory CD4 T cells typically arise during the first two weeks of acute infection. Unlike most viruses, cytomegalovirus (CMV) exhibits an extended persistent replication phase followed by lifelong latency accompanied with some gene expression. We show that during mouse CMV (MCMV) infection, CD4 T cells recognizing an epitope derived from the viral M09 protein only develop after conventional memory T cells have already peaked and contracted. Ablating these CD4 T cells by mutating the M09 genomic epitope in the MCMV Smith strain, or inducing them by introducing the epitope into the K181 strain, resulted in delayed or enhanced control of viral persistence, respectively. These cells were shown to be unique compared to their conventional memory counterparts; producing higher IFNγ and IL-2 and lower IL-10 levels. RNAseq analyses revealed them to express distinct subsets of effector genes as compared to classical CD4 T cells. Additionally, when M09 cells were induced by epitope vaccination they significantly enhanced protection when compared to conventional CD4 T cells alone. These data show that late-rising CD4 T cells are a unique memory subset with excellent protective capacities that display a development program strongly differing from the majority of memory T cells. Author summary: Functional memory T cells are critical to ultimately control chronic viral infection. We show that cytomegalovirus (CMV) induces a population of unique memory CD4 T cells that expand late during infection and resolve viral persistence much better than conventional T memory cells. Mutation of the genomic CMV epitope recognized by these T cells results in markedly enhanced persistent replication, and introduction of the epitope into a CMV strain that lacks it induces much quicker resolution of persistence. When induced via vaccination, we show these T cells provide significantly enhanced protection against acute viral challenge. Together our study identifies a novel population of CD4 T cells that utilize distinct effector function(s) to rapidly resolve persistent viral replication. [ABSTRACT FROM AUTHOR]

Urgent dermatology review was sought for a neonate born at term via emergency caesarean section for reduced movements. The pregnancy was complicated by gestational diabetes and infection with suspected coxsackie virus in the second trimester. There were 15 purple/blue nodules consistent with "blueberry muffin syndrome" and associated anaemia (118 g/L). Due to hypoxia, she was given antibiotics for suspected sepsis. TORCH screen was negative and USS abdomen and cranium were normal. A blood film showed B cell aplasia and LDH was raised (710 unit/L). CXR showed a mediastinal mass, left pleural effusion and left lung opacity. A skin biopsy was taken, chest drain placed and the baby transferred to Great Ormond Street. She was subsequently diagnosed with acute myeloid leukaemia following bone marrow and lumbar puncture. All three skin biopsies showed a malignant infiltrate with one displaying positivity for CD12 and CD33. CT and MRI scans have shown widespread nodules in the lungs, liver, kidneys, bones and intra-cranially. She is being treated with chemotherapy which has been complicated by a cardiac arrest and severe mucositis leading to colostomy. She is also NG fed and has sensorineural hearing loss. The nodules seen in "blueberry muffin syndrome" are most commonly extramedullary erythropoiesis but can also represent purpura or metastases. The causes are congenital infections, blood disorders or tumours. There is frequently associated anaemia (as in our case) and hepatosplenomegaly. This case demonstrates a rare and concerning cause of the syndrome and highlights the role dermatologists can play in diagnosis. [ABSTRACT FROM AUTHOR]

We report the case of a 9-year-old girl who presented with asymptomatic lesions on the extensor surfaces of the elbows and knees, in keeping with tuberous xanthoma. She was investigated and diagnosed with homozygous familial hypercholesterolaemia, and commenced on lipid-lowering treatment. LDL-C lowering has also been achieved via use of drugs such as lomitapide, which inhibit microsomal triglyceride transfer protein and hence decrease synthesis of LDL. [Extracted from the article]

Hidradenitis suppurativa (HS) is a chronic relapsing, remitting disease which results in the formation of inflammatory nodules and pustules in intertriginous areas. HS is a complex disease with known psychosocial impact. Adalimumab is a biologic, used for treatment resistant HS, which working by inactivating TNF‐alpha. Our primary objective was to determine the effects of adalimumab on HS‐PGA and DLQI scores in patients with HS that had been on the treatment for at least 6 months. Our secondary objective was to note and assess the significance of adverse effects and impacts on wider health, namely occupational and social. A retrospective cross‐sectional study was performed using clinic notes from routine follow ups in biologic clinics in three specialist HS centers. About 77% (n = 78/101) patients demonstrated improvements in their HS‐PGA scores. Significant improvements in the DLQI scores of the patient cohort (P =.0001, 95% CI −12.8 to −5.9) have also been demonstrated. A total of 31.7% (32/101) patients experienced adverse effects spanning multiple organ systems, with 27.7% (28/101) requiring treatment cessation. Three of these patients stopped due to the worsening of preexisting mental health symptoms. Adalimumab is effective in reducing HS‐PGA and DLQI scores, but patients still complain of systemic effects necessitating drug cessation in some instances. A holistic and multisystemic approach to follow up is required, and there is scope for further studies examining temporal causality in the context of adalimumab and its multisystemic physical and psychological effects. [ABSTRACT FROM AUTHOR]

In the wake of World War II, policymakers in nations such as the United States, along with the leaders, staff, and representatives to the Food and Agriculture Organization of the United Nations (FAO), sought to understand and address the short- and long-term causes of food and agricultural problems. This article examines the ways that tensions between national sovereignty and international problem-solving prevented the creation of a worldfood reserve that could be used to address food crises. For almost a decade, multiple leaders of FAO and panels of experts endorsed the value of establishing some form of reserve that the world could rely on in times of food emergencies. Through three waves of activity in the years after World War II--beginning with the ambitious World Food Board, the more limited International Commodity Clearing House, and the multiple expert-generated plans, including the exceptionally flexible Plan of Three Circles--FAO policymakers and planners were unable to overcome the reluctance of member nations to give up national control over even a limited aspect of agriculture and food production. This article examines the proposals made by FAO between 1946 and 1953 to explore the challenges between state control over agricultural production and international efforts to establish a world food reserve--challenges that persist today. Ultimately, we see that in order to better address global food insecurity, we must understand this critical tension between national sovereignty and international action. [ABSTRACT FROM AUTHOR]

Several innate sensing pathways contribute to the control of early cytomegalovirus (CMV) infection, leading to a multiphasic type I interferon (IFN-I) response that limits viral replication and promotes host defenses. Toll-like receptor (TLR)-dependent pathways induce IFN-I production in CMV-infected plasmacytoid dendritic cells; however, the initial burst of IFN-I that occurs within the first few hours in vivo is TLR independent and emanates from stromal cells. Here we show that primary human endothelial cells mount robust IFN-I responses to human CMV that are dependent upon cyclic GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3) signaling. Disruption of STING expression in endothelial cells by clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 revealed that it is essential for the induction of IFN-I and restriction of CMV replication. Consistently, STING was necessary to mount the first phase of IFN-I production and curb CMV replication in infected mice. Thus, DNA sensing through STING is critical for primary detection of both human and mouse CMV in nonhematopoietic cells and drives the initial wave of IFN-I that is key for controlling early viral replication in vivo. [ABSTRACT FROM AUTHOR]

TNF-related apoptosis inducing ligand (TRAIL) death receptors (DR) regulate apoptosis and inflammation, but their role in antiviral defense is poorly understood. Cytomegaloviruses (CMV) encode many immune-modulatory genes that shape host immunity, and they utilize multiple strategies to target the TNF-family cytokines. Here we show that the m166 open reading frame (orf) of mouse CMV (MCMV) is strictly required to inhibit expression of TRAIL-DR in infected cells. An MCMV mutant lacking m166 expression (m166stop) is severely compromised for replication in vivo, most notably in the liver, and depleting natural killer (NK) cells, or infecting TRAIL-DR−/− mice, restored MCMV-m166stop replication completely. These results highlight the critical importance for CMV to have evolved a strategy to inhibit TRAIL-DR signaling to thwart NK-mediated defenses. [ABSTRACT FROM AUTHOR]

No-take marine protected areas (MPAs) represent an effective biodiversity conservation tool for a range of species including resident reef fishes that are intrinsically vulnerable to overfishing and other localised impacts. The western blue groper (Achoerodus gouldii) is the largest permanent-resident reef teleost in southern Australian waters and has the second-oldest recorded age of any labrid at 70 years. Acoustic telemetry was used to investigate whether adult A. gouldii can be effectively protected within adequately sized no-take MPAs. Ten passive acoustic receivers tracked the movements of 15 A. gouldii individuals (69-112-cm total length; 7-31-kg weight) at a site off north-western Kangaroo Island, South Australia. Most of the fish displayed high site fidelity (91-100% residence time for 10 of the 11 fish with useful data) for a narrow strip of fringing coastal reef (~1-km length by ~40-m width) throughout a 12-month period. Mean home-range along-shore length and area were estimated at 1076 ± 83 m (s.e.), and 45 188 ± 3497 m², respectively (n = 11 fish with useful data). Comparison with other resident temperate-reef teleosts indicated no relationship between fish length and home-range area, and that A. gouldii has a relatively small home range. The high site fidelity and small home range of adult A. gouldii individuals makes localised populations amenable to a high level of protection within no-take MPAs. The western blue groper (Achoerodus gouldii) is a large, long-lived fish that is intrinsically vulnerable to overfishing and other localised impacts. A 12-month acoustic tracking study aimed at determining the movements of adult A. gouldii confirmed that individuals are highly amenable to protection within adequately sized and appropriately located no-take marine protected areas. For one of the largest temperate-reef fishes so far tracked using acoustic technology, A. gouldii has a relatively small home range. [ABSTRACT FROM AUTHOR]

Many analysts argue that the potential for a natural, accidental, or nefarious infectious disease event to have a dramatic impact on urban areas in the United States and abroad is growing. After reviewing the justification for this position, this article considers what cities should do to prepare for a major disease event. Recognizing that prevention and preparation receive insufficient attention, we recommend that planners seek out and work with both public and private sector groups with roles in disaster planning; design land and transportation planning information systems to aid and support decision makers during crises; encourage greater self-sufficiency in food production and consumption; assist in the design of humane, realistic evacuation strategies and routes; and consider the effects of their day-to-day recommendations on disease risk and response. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) establishes a lifelong infection facilitated, in part, by circumventing immune defenses mediated by tumor necrosis factor (TNF)-family cytokines. An example of this is the mouse CMV (MCMV) m166 protein, which restricts expression of the TNF-related apoptosis-inducing ligand (TRAIL) death receptors, promoting early-phase replication. We show here that replication of an MCMV mutant lacking m166 is also severely attenuated during viral persistence in the salivary glands (SG). Depleting group I innate lymphoid cells (ILCs) or infecting Trail−/− mice completely restored persistent replication of this mutant. Group I ILCs are comprised of two subsets, conventional natural killer cells (cNK) and tissue-resident cells often referred to as innate lymphoid type I cells (ILC1). Using recently identified phenotypic markers to discriminate between these two cell types, their relative expression of TRAIL and gamma interferon (IFN-γ) was assessed during both early and persistent infection. ILC1 were found to be the major TRAIL expressers during both of these infection phases, with cNK expressing very little, indicating that it is ILC1 that curtail replication via TRAIL in the absence of m166-imposed countermeasures. Notably, despite high TRAIL expression by SG-resident ILC1, IFN-γ production by both ILC1 and cNK was minimal at this site of viral persistence. Together these results highlight TRAIL as a key ILC1-utilized effector molecule that can operate in defense against persistent infection at times when other innate control mechanisms may be muted and highlight the importance for the evolution of virus-employed countermeasures. IMPORTANCE Cytomegalovirus (a betaherpesvirus) is a master at manipulating immune responses to promote its lifelong persistence, a result of millions of years of coevolution with its host. Using a one-of-a-kind MCMV mutant unable to restrict expression of the TNF-related apoptosis-inducing ligand death receptors (TRAIL-DR), we show that TRAIL-DR signaling significantly restricts both early and persistent viral replication. Our results also reveal that these defenses are employed by TRAIL-expressing innate lymphoid type I cells (ILC1) but not conventional NK cells. Overall, our results are significant because they show the key importance of viral counterstrategies specifically neutralizing TRAIL effector functions mediated by a specific, tissue-resident subset of group I ILCs. [ABSTRACT FROM AUTHOR]

Cardif, also known as IPS-1, VISA, and MAVS, is an intracellular adaptor protein that functions downstream of the retinole acidinducible gene I family of pattern recognition receptors. Cardif is required for the production of type I IFNs and other inflammatory cytokines after retinoic acid-inducible gene I-Iike receptors recognize intracellular antigenic RNA. Studies have recently shown that Cardif may have other roles in the immune system in addition to its role in viral immunity. In this study, we find that the absence of Cardif alters normal NK cell development and maturation. Cardiff-/- mice have a 35% loss of mature CD27- CD11b+ NK cells in the periphery. In addition, Cardif-/- NK cells have altered surface marker expression, lower cytotoxicity, decreased intracellular STATI levels, increased apoptosis, and decreased proliferation compared with wild-type NK cells. Mixed chimeric mice revealed that the defective maturation and increased apoptotic rate of peripheral Cardif-/- NK cells is cell intrinsic. However, Cardif-/- mice showed enhanced control of mouse CMV (a DNA β-herpesvirus) by NK cells, commensurate with increased activation and IFN-" production by these immature NK cell subsets. These results indicate that the skewed differentiation and altered STAT expression of Cardif-/- NK cells can result in their hyperresponsiveness in some settings and support recent findings that Cardif-dependent signaling can regulate aspects of immune cell development and/or function distinct from its well-characterized role in mediating cell-intrinsic defense to RNA viruses. [ABSTRACT FROM AUTHOR]

Abstract: An enduring challenge for community ecologists is to understand how different assemblages of species are derived from a common pool of potential colonists. Early colonisers can affect the ability of subsequent arrivals to colonise and persist, and thereby influence the development and structure of the resulting assemblage. In two independent experiments, we tested for such historical effects of priority on the assemblages of mobile fauna colonising artificial seagrass initially occupied by epibiota (algae and sessile invertebrates) and/or predatory Palaemonid shrimp. Multivariate analyses detected strong priority effects of both epibiota and Palaemonids on the structure of faunal assemblages as early as 5 days, and up to 45 days after experimental treatments were established, even though initial conditions (i.e. abundances of epibiota and Palaemonids) had become similar among treatments. The abundances of key taxa, identified by SIMPER analyses as those taxa contributing the most to multivariate differences among treatments, were typically enhanced where epibiota were initially present. In contrast, prior colonisation by Palaemonid shrimp produced subtle and variable effects on individual taxa. Nevertheless, these experiments provide evidence for priority effects and demonstrate how variation in the structure of contemporary assemblages can be intimately linked with key historical events that occurred during their development, but may no longer be apparent. Consequently, our ability to interpret variation among contemporary assemblages may be enhanced when contemporary patterns are viewed within an historical context. [Copyright &y& Elsevier]

CD4 T cells provide protection against cytomegalovirus (CMV) and other persistent viruses, and the ability to quantify and characterize epitope-specific responses is essential to gain a more precise understanding of their effector roles in this regard. Here, we report the first two I-Ad-restricted CD4 T cell responses specific for mouse CMV (MCMV) epitopes and use a major histocompatibility complex class II (MHC-II) tetramer to characterize their phenotypes and functions. We demonstrate that MCMV-specific CD4 T cells can express high levels of granzyme B and kill target cells in an epitope-and organ-specific manner. In addition, CD4 T cell epitope vaccination of immunocompetent mice reduced MCMV replication in the same organs where CD4 cytotoxic T lymphocyte (CTL) activity was observed. Together, our studies show that MCMV epitope-specific CD4 T cells have the potential to mediate antiviral defense by multiple effector mechanisms in vivo. [ABSTRACT FROM AUTHOR]

T cells undergo extensive chromatin remodeling over several days following stimulation through the T cell receptor. However, the kinetics and gene loci targeted by early remodeling events within the first 24 hours of T cell priming to orchestrate effector differentiation have not been well described. We identified that chromatin accessibility is rapidly and extensively remodeled within 1 hour of stimulation of naïve CD8 + T cells, leading to increased global chromatin accessibility at many effector T cell-associated genes that are enriched for AP-1, early growth response (EGR), and nuclear factor of activated T cells (NFAT) binding sites, but this short duration of stimulation is insufficient for commitment to clonal expansion in vivo . Sustained 24-hour stimulation led to further chromatin remodeling and was sufficient to enable clonal expansion. These data suggest that the duration of antigen receptor signaling is intimately coupled to chromatin remodeling and activation of genes involved in effector cell differentiation and highlight a potential mechanism that helps CD8 + T cells discriminate between foreign- and self-antigens., (Copyright ©2023, Yale Journal of Biology and Medicine.)

CD8 + T cells provide host protection against pathogens by differentiating into distinct effector and memory cell subsets, but how chromatin is site-specifically remodeled during their differentiation is unclear. Due to its critical role in regulating chromatin and enhancer accessibility through its nucleosome remodeling activities, we investigated the role of the canonical BAF (cBAF) chromatin remodeling complex in antiviral CD8 + T cells during infection. ARID1A, a subunit of cBAF, was recruited early after activation and established de novo open chromatin regions (OCRs) at enhancers. Arid1a deficiency impaired the opening of thousands of activation-induced enhancers, leading to loss of TF binding, dysregulated proliferation and gene expression, and failure to undergo terminal effector differentiation. Although Arid1a was dispensable for circulating memory cell formation, tissue-resident memory (Trm) formation was strongly impaired. Thus, cBAF governs the enhancer landscape of activated CD8 + T cells that orchestrates TF recruitment and activity and the acquisition of specific effector and memory differentiation states., Competing Interests: Declaration of interests S.M.K. is on the scientific advisory boards and has equity in EvolveImmune Therapeutics, Affini-T Therapeutics, Arvinas, and Pfizer., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Atopic eczema is a common and complex disease. Missing genetic hereditability and increasing prevalence in industrializing nations point toward an environmental driver. We investigated the temporal association of weather and pollution parameters with eczema severity. This cross-sectional clinical study was performed between May 2018 and March 2020 and is part of the Tower Hamlets Eczema Assessment. All participants had a diagnosis of eczema, lived in East London, were of Bangladeshi ethnicity, and were aged <31 years. The primary outcome was the probability of having an Eczema Area and Severity Index score > 10 after previous ambient exposure to commonly studied meteorological variables and pollutants. There were 430 participants in the groups with Eczema Area and Severity Index ≤ 10 and 149 in those with Eczema Area and Severity Index > 10. Using logistic generalized additive models and a model selection process, we found that tropospheric ozone averaged over the preceding 270 days was strongly associated with eczema severity alongside the exposure to fine particles with diameters of 2.5 μm or less (fine particulate matter) averaged over the preceding 120 days. In our models and analyses, fine particulate matter appeared to largely act in a supporting role to ozone. We show that long-term exposure to ground-level ozone at high levels has the strongest association with eczema severity., (Crown Copyright © 2021 Published by Elsevier Inc. on behalf of the Society for Investigative Dermatology.)

Immunological memory is a hallmark of adaptive immunity that confers long-lasting protection from reinfections. Memory CD8 + T cells provide protection by actively scanning for their cognate antigen and migrating into inflamed tissues. Trafficking patterns of CD8 + T cells are also a major determinant of cell fate outcomes during differentiation into effector and memory cell states. CD8 + T-cell trafficking must therefore be dynamically and tightly regulated to ensure that CD8 + T cells arrive at the correct locations and differentiate to acquire appropriate effector functions. This review aims to discuss the importance of CD8 + T-cell trafficking patterns in regulating effector and memory differentiation, maintenance, and reactivation., (Copyright © 2021 Cold Spring Harbor Laboratory Press; all rights reserved.)

A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8 + tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8 + TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8 + TILs, which also correlated with progressive T cell dysfunction. Cd36 -/- T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8 + TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8 + T cell dysfunction and serves as a therapeutic avenue for immunotherapies., Competing Interests: Declaration of interests G.C. receives research funding from Bayer AG and Boehringer Ingelheim, but the funding is not relevant to the current study. J.L.W. and X.S. are named inventors on patent applications or patents related to the use of oxidation-specific antibodies held by UCSD. R.Z. is an inventor on patent applications related to work on GITR, PD-1, and CTLA-4. R.Z. is a consultant for Leap Therapeutics and iTEOS. T.M. is a cofounder and holds equity in IMVAQ Therapeutics. T.M. is a consultant for Immunos Therapeutics, Pfizer, and Immunogenesis. T.M. has research support from Bristol-Myers Squibb; Surface Oncology; Kyn Therapeutics; Infinity Pharmaceuticals, Inc.; Peregrine Pharmaceuticals, Inc.; Adaptive Biotechnologies; Leap Therapeutics, Inc.; and Aprea. T.M. has patents on applications related to work on oncolytic viral therapy, alpha virus-based vaccines, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. J.D.W. is a consultant for Adaptive Biotech, Amgen, Apricity, Ascentage Pharma, Astellas, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chugai, Elucida, Eli Lilly, F Star, Georgiamune, Imvaq, Kyowa Hakko Kirin, Linneaus, Merck Pharmaceuticals, Neon Therapeutics, Polynoma, Psioxus, Recepta, Takara Bio, Trieza, Truvax, Sellas Life Sciences, Serametrix, Surface Oncology, Syndax, Syntalogic, and Werewolf Therapeutics. J.D.W. reports grants from Bristol Myers Squibb and Sephora. J.D.W. has equity in Tizona Pharmaceuticals, Adaptive Biotechnologies, Imvaq, Beigene, Linneaus, Apricity, Arsenal IO, and Georgiamune. J.D.W. is an inventor on patent applications related to work on DNA vaccines in companion animals with cancer, assays for suppressive myeloid cells in blood, oncolytic viral therapy, alphavirus-based vaccines, neo-antigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4., (Copyright © 2021 Elsevier Inc. All rights reserved.)

FOXP3 + regulatory T cells (Treg) play a critical role in mediating tolerance to self-antigens and can repress antitumor immunity through multiple mechanisms. Therefore, targeted depletion of tumor-resident Tregs is warranted to promote effective antitumor immunity while preserving peripheral homeostasis. Here, we propose the chemokine receptor CCR8 as one such optimal tumor Treg target. CCR8 was expressed by Tregs in both murine and human tumors, and unlike CCR4, a Treg depletion target in the clinic, CCR8 was selectively expressed on suppressive tumor Tregs and minimally expressed on proinflammatory effector T cells (T eff ). Preclinical mouse tumor modeling showed that depletion of CCR8 + Tregs through an FcyR-engaging anti-CCR8 antibody, but not blockade, enabled dose-dependent, effective, and long-lasting antitumor immunity that synergized with PD-1 blockade. This depletion was tumor Treg-restricted, sparing CCR8 + T cells in the spleen, thymus, and skin of mice. Importantly, Fc-optimized, nonfucosylated (nf) anti-human CCR8 antibodies specifically depleted Tregs and not T effs in ex vivo tumor cultures from primary human specimens. These findings suggest that anti-CCR8-nf antibodies may deliver optimal tumor-targeted Treg depletion in the clinic, providing long-term antitumor memory responses while limiting peripheral toxicities. SIGNIFICANCE: These findings show that selective depletion of regulatory T cells with an anti-CCR8 antibody can improve antitumor immune responses as a monotherapy or in combination with other immunotherapies. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/11/2983/F1.large.jpg., (©2021 American Association for Cancer Research.)

In response to infection, T cells adopt a range of differentiation states, creating numerous heterogeneous subsets that exhibit different phenotypes, functions, and migration patterns. This T cell heterogeneity is a universal feature of T cell immunity, needed to effectively control pathogens in a context-dependent manner and generate long-lived immunity to those pathogens. Here, we review new insights into differentiation state dynamics and population heterogeneity of CD8+ T cells in acute and chronic viral infections and cancer and highlight the parallels and distinctions between acute and chronic antigen stimulation settings. We focus on transcriptional and epigenetic networks that modulate the plasticity and terminal differentiation of antigen-specific CD8+ T cells and generate functionally diverse T cell subsets with different roles to combat infection and cancer., Competing Interests: Disclosures: S.M. Kaech reported personal fees from Celsius Therapeutics and EvolveImmune outside the submitted work. No other disclosures were reported., (© 2021 Chung et al.)