Regulatory T cells (Tregs) and the PD-1: PD-ligand (PD-L) pathway are both critical to terminating immune responses. Elimination of either can result in the breakdown of tolerance and the development ...of autoimmunity. The PD-1: PD-L pathway can thwart self-reactive T cells and protect against autoimmunity in many ways. In this review, we highlight how PD-1 and its ligands defend against potentially pathogenic self-reactive effector T cells by simultaneously harnessing two mechanisms of peripheral tolerance: (i) the promotion of Treg development and function and (ii) the direct inhibition of potentially pathogenic self-reactive T cells that have escaped into the periphery. Treg cells induced by the PD-1 pathway may also assist in maintaining immune homeostasis, keeping the threshold for T-cell activation high enough to safeguard against autoimmunity. PD-L1 expression on non-hematopoietic cells as well as hematopoietic cells endows PD-L1 with the capacity to promote Treg development and enhance Treg function in lymphoid organs and tissues that are targets of autoimmune attack. At sites where transforming growth factor-β is present (e.g. sites of immune privilege or inflammation), PD-L1 may promote the de novo generation of Tregs. When considering the consequences of uncontrolled immunity, it would be therapeutically advantageous to manipulate Treg development and sustain Treg function. Thus, this review also discusses how the PD-1 pathway regulates a number of autoimmune diseases and the therapeutic potential of PD-1: PD-L modulation.
The receptor CTLA-4 has been implicated in controlling B cell responses, but the mechanisms by which CTLA-4 regulates antibody production are not known. Here we showed deletion of CTLA-4 in adult ...mice increased Tfh and Tfr cell numbers and augmented B cell responses. In the effector phase, loss of CTLA-4 on Tfh cells resulted in heightened B cell responses, whereas loss of CTLA-4 on Tfr cells resulted in defective suppression of antigen-specific antibody responses. We also found that non-Tfr Treg cells could suppress B cell responses through CTLA-4 and that Treg and/or Tfr cells might downregulate B7-2 on B cells outside germinal centers as a means of suppression. Within the germinal center, however, Tfr cells potently suppress B cells through CTLA-4, but with a mechanism independent of altering B7-1 or B7-2. Thus, we identify multifaceted regulatory roles for CTLA-4 in Tfh, Tfr, and Treg cells, which together control humoral immunity.
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•CTLA-4 inhibits Tfh and Tfr cell differentiation and/or maintenance•Treg and/or Tfr cells suppress extrafollicular B cell B7-2 expression•CTLA-4 inhibits Tfh stimulation of B cell responses•Tfr cells suppress GC B cells through CTLA-4, but not by altering B7-2 levels
The role of the inhibitory receptor CTLA-4 in controlling B cell responses is still unclear. Sharpe and colleagues show that CTLA-4 controls B cell responses by regulating Tfh, Tfr, and Treg cell differentiation and effector function.
Obesity is a major cancer risk factor, but how differences in systemic metabolism change the tumor microenvironment (TME) and impact anti-tumor immunity is not understood. Here, we demonstrate that ...high-fat diet (HFD)-induced obesity impairs CD8+ T cell function in the murine TME, accelerating tumor growth. We generate a single-cell resolution atlas of cellular metabolism in the TME, detailing how it changes with diet-induced obesity. We find that tumor and CD8+ T cells display distinct metabolic adaptations to obesity. Tumor cells increase fat uptake with HFD, whereas tumor-infiltrating CD8+ T cells do not. These differential adaptations lead to altered fatty acid partitioning in HFD tumors, impairing CD8+ T cell infiltration and function. Blocking metabolic reprogramming by tumor cells in obese mice improves anti-tumor immunity. Analysis of human cancers reveals similar transcriptional changes in CD8+ T cell markers, suggesting interventions that exploit metabolism to improve cancer immunotherapy.
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•Defined a metabolic single-cell atlas of the tumor immune landscape with obesity•Obesity induces a metabolic tug of war between tumor and T cells for lipids•Tumor cells induce fat metabolism and change their microenvironment during obesity•Blocking metabolic adaptations to obesity in cancers restores anti-tumor immunity
High-fat diet compromises anti-tumor immunity by interfering with metabolism in the tumor microenvironment.
Naive T cell stimulation activates anabolic metabolism to fuel the transition from quiescence to growth and proliferation. Here we show that naive CD4+ T cell activation induces a unique program of ...mitochondrial biogenesis and remodeling. Using mass spectrometry, we quantified protein dynamics during T cell activation. We identified substantial remodeling of the mitochondrial proteome over the first 24 hr of T cell activation to generate mitochondria with a distinct metabolic signature, with one-carbon metabolism as the most induced pathway. Salvage pathways and mitochondrial one-carbon metabolism, fed by serine, contribute to purine and thymidine synthesis to enable T cell proliferation and survival. Genetic inhibition of the mitochondrial serine catabolic enzyme SHMT2 impaired T cell survival in culture and antigen-specific T cell abundance in vivo. Thus, during T cell activation, mitochondrial proteome remodeling generates specialized mitochondria with enhanced one-carbon metabolism that is critical for T cell activation and survival.
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•T cell activation initiates synchronized mitochondrial biogenesis•Quantitative proteomics defined mitochondrial proteome remodeling•One-carbon metabolism was the most-induced mitochondrial pathway•Genetic inhibition of mitochondrial one-carbon metabolism impaired T cells
Ron-Harel et al. (2016) reveal that naive T cell activation induces a highly synchronized program of mitochondrial biogenesis and proteome remodeling, giving rise to a distinct population of mitochondria with enhanced 1C metabolism. Inhibition of mitochondrial 1C metabolism impairs T cell survival and antigen-specific T cell abundance.
Defective antibody production in aging is broadly attributed to immunosenescence. However, the precise immunological mechanisms remain unclear. Here, we demonstrate an increase in the ratio of ...inhibitory T follicular regulatory (TFR) cells to stimulatory T follicular helper (TFH) cells in aged mice. Aged TFH and TFR cells are phenotypically distinct from those in young mice, exhibiting increased programmed cell death protein-1 expression but decreased ICOS expression. Aged TFH cells exhibit defective antigen-specific responses, and programmed cell death protein-ligand 1 blockade can partially rescue TFH cell function. In contrast, young and aged TFR cells have similar suppressive capacity on a per-cell basis in vitro and in vivo. Together, these studies reveal mechanisms contributing to defective humoral immunity in aging: an increase in suppressive TFR cells combined with impaired function of aged TFH cells results in reduced T-cell-dependent antibody responses in aged mice.
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•Stimulatory TFH and inhibitory TFR cells expand with age, with higher TFR:TFH ratios•TFH cells from aged mice show defects in antigen-specific B cell help•Aged and young TFR cells have equal suppressive capacity•Impaired TFH and increased TFR cells result in diminished B cell responses in aging
Humoral immunity wanes with age. Using in vitro and in vivo models, Sage et al. determine that defective T-cell-dependent B cell responses associated with aging result from an overabundance of fully suppressive TFR cells and impaired antigen-specific TFH cell responses.
Conspectus Electrochemical sensors have the potential to achieve sensitive, specific, and low-cost detection of biomoleculesa capability that is ever more relevant to the diagnosis and monitored ...treatment of disease. The development of devices for clinical diagnostics based on electrochemical detection could provide a powerful solution for the routine use of biomarkers in patient treatment and monitoring and may overcome the many issues created by current methods, including the long sample-to-answer times, high cost, and limited prospects for lab-free use of traditional polymerase chain reaction, microarrays, and gene-sequencing technologies. In this Account, we summarize the advances in electrochemical biomolecular detection, focusing on a new and integrated platform that exploits the bottom-up fabrication of multiplexed electrochemical sensors composed of electrodeposited noble metals. We trace the evolution of these sensors from gold nanoelectrode ensembles to nanostructured microelectrodes (NMEs) and discuss the effects of surface morphology and size on assay performance. The development of a novel electrocatalytic assay based on Ru3+ adsorption and Fe3+ amplification at the electrode surface as a means to enable ultrasensitive analyte detection is discussed. Electrochemical measurements of changes in hybridization events at the electrode surface are performed using a simple potentiostat, which enables integration into a portable, cost-effective device. We summarize the strategies for proximal sample processing and detection in addition to those that enable high degrees of sensor multiplexing capable of measuring 100 different analytes on a single chip. By evaluating the cost and performance of various sensor substrates, we explore the development of practical lab-on-a-chip prototype devices. By functionalizing the NMEs with capture probes specific to nucleic acid, small molecule, and protein targets, we can successfully detect a wide variety of analytes at clinically relevant concentrations and speeds. Using this platform, we have achieved attomolar detection levels of nucleic acids with overall assay times as short as 2 min. We also describe the adaptation of the sensing platform to allow for the measurement of uncharged analytesa challenge for reporter systems that rely on the charge of an analyte. Furthermore, the capabilities of this system have been applied to address the many current and important clinical challenges involving the detection of pathogenic species, including both bacterial and viral infections and cancer biomarkers. This novel electrochemical platform, which achieves large molecular-to-electrical amplification by means of its unique redox-cycling readout strategy combined with rapid and efficient analyte capture that is aided by nanostructured microelectrodes, achieves excellent specificity and sensitivity in clinical samples in which analytes are present at low concentrations in complex matrices.
Follicular regulatory T (Tfr) cells are a regulatory T cell subset that controls antibody production by inhibiting T follicular helper (Tfh)-mediated help to B cells. Tfh and Tfr cells possess ...opposing functions suggesting unique programming. Here we elucidated the transcriptional program controlling Tfr suppressive function. We found that Tfr cells have a program for suppressive function fine-tuned by tissue microenvironment. The transcription factor FoxP3 and chromatin-modifying enzyme EZH2 are essential for this transcriptional program but regulate the program in distinct ways. FoxP3 modifies the Tfh program to induce a Tfr-like functional state, demonstrating that Tfr cells coopt the Tfh program for suppression. Importantly, we identified a Tfr cell population that loses the Tfr program to become "ex-Tfr" cells with altered functionality. These dysfunctional ex-Tfr cells may have roles in modulating pathogenic antibody responses. Taken together, our studies reveal mechanisms controlling the Tfr transcriptional program and how failure of these mechanisms leads to dysfunctional Tfr cells.
Background
The benefit of surveillance colonoscopy in older adults is not well described.
Aims
To quantify the detection of colorectal cancer (CRC) and advanced polyps during surveillance colonoscopy ...in older adults with a history of colon polyps.
Methods
We conducted a systematic review (MEDLINE, Cochrane Library, Web of Science, and Embase) for all published studies through May 2020 in adults age > 70 undergoing surveillance colonoscopy. The main outcome was CRC and advanced polyps detection. We performed meta-analysis to pool results by age (>70 vs. 50–70).
Results
The search identified 6239 studies, of which 569 underwent full-text review and 64 data abstraction, of which 19 were included. The risk of detecting CRC (
N
= 11) was higher in those >70 compared to 50–70 (risk ratio 1.5 (95% CI 1.1–2.2); risk difference 0.8% (95% CI −0.2%–1.8%)). Similarly, the risk of detecting advanced polyps (
N
= 8) was higher in those >70 compared to 50–70 (risk ratio 1.3 (95% CI 1.2–1.3), risk difference 2.7% (95% CI 1.3%–4.0%)). Most studies did not stratify results by baseline polyp risk.
Conclusions
The detection of CRC and advanced polyps during surveillance colonoscopy in older individuals was higher than in younger controls; however, the absolute risk increase for both was small. These differences must be weighed against competing medical problems and limited life expectancy in older adults when making decisions about surveillance colonoscopy. More primary data on the risks of CRC and advanced polyps accounting for number of past colonoscopies, prior polyp risk, and duration of time since last polyp are needed.
The Saccharomyces Genome Database (SGD) is a well-established, key resource for researchers studying Saccharomyces cerevisiae. In addition to updating and maintaining the official genomic sequence of ...this highly studied organism, SGD provides integrated data regarding gene functions and phenotypes, which are extracted from the published literature. The vast amount and variety of data housed in the database can prove challenging to navigate for the first-time user. Therefore, this chapter serves as an introduction describing how to search the database in order to discover new information. We introduce the different types of pages on the website, and describe how to manipulate the tables and diagrams therein to display, download, or analyze the data using various SGD tools.
Ex vivo lung perfusion (EVLP) is a data-intensive platform used for the assessment of isolated lungs outside the body for transplantation; however, the integration of artificial intelligence to ...rapidly interpret the large constellation of clinical data generated during ex vivo assessment remains an unmet need. We developed a machine-learning model, termed InsighTx, to predict post-transplant outcomes using n = 725 EVLP cases. InsighTx model AUROC (area under the receiver operating characteristic curve) was 79 ± 3%, 75 ± 4%, and 85 ± 3% in training and independent test datasets, respectively. Excellent performance was observed in predicting unsuitable lungs for transplantation (AUROC: 90 ± 4%) and transplants with good outcomes (AUROC: 80 ± 4%). In a retrospective and blinded implementation study by EVLP specialists at our institution, InsighTx increased the likelihood of transplanting suitable donor lungs odds ratio=13; 95% CI:4-45 and decreased the likelihood of transplanting unsuitable donor lungs odds ratio=0.4; 95%CI:0.16-0.98. Herein, we provide strong rationale for the adoption of machine-learning algorithms to optimize EVLP assessments and show that InsighTx could potentially lead to a safe increase in transplantation rates.
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