ABSTRACT
The ecto-ATPase CD39 is expressed on exhausted CD8+ T cells in chronic viral infection and has been proposed as a marker of tumor-specific CD8+ T cells in cancer, but the role of CD39 in an effector and memory T cell response has not been clearly defined. We report that CD39 is expressed on Ag-specific CD8+ short-lived effector cells, while it's co-ectoenzyme, CD73, is found on memory precursor effector cells (MPECs) in vivo. Inhibition of CD39 enzymatic activity during in vitro T cell priming enhances MPEC differentiation in vivo after transfer and infection. The enriched MPEC phenotype is associated with enhanced tissue resident memory T cell (TRM cell) establishment in the brain and salivary gland following an acute intranasal viral infection, suggesting that CD39 ATPase activity plays a role in memory CD8+ T cell differentiation. We also show that CD39 is expressed on human and murine TRM cells across several nonlymphoid tissues and melanoma, whereas CD73 is expressed on both circulating and resident memory subsets in mice. In contrast to exhausted CD39+ T cells in chronic infection, CD39+ TRM cells are fully functional when stimulated ex vivo with cognate Ag, further expanding the identity of CD39 beyond a T cell exhaustion marker.
Subject(s)
Antigens, CD , Apyrase , CD8-Positive T-Lymphocytes , Cell Differentiation , Memory T Cells , Animals , Apyrase/immunology , Apyrase/metabolism , Mice , CD8-Positive T-Lymphocytes/immunology , Antigens, CD/metabolism , Antigens, CD/immunology , Humans , Memory T Cells/immunology , Cell Differentiation/immunology , Immunologic Memory/immunology , Mice, Inbred C57BL , 5'-Nucleotidase/metabolism , 5'-Nucleotidase/immunologyABSTRACT
Resident memory T cells (T RM ) have been described in barrier tissues as having a 'sensing and alarm' function where, upon sensing cognate antigen, they alarm the surrounding tissue and orchestrate local recruitment and activation of immune cells. In the immunologically unique and tightly restricted CNS, it remains unclear if and how brain T RM , which express the inhibitory receptor PD-1, alarm the surrounding tissue during antigen re-encounter. Here, we reveal that T RM are sufficient to drive the rapid remodeling of the brain immune landscape through activation of microglia, DCs, NK cells, and B cells, expansion of Tregs, and recruitment of macrophages and monocytic dendritic cells. Moreover, we report that while PD-1 restrains granzyme B expression by reactivated brain T RM , it has no effect on cytotoxicity or downstream alarm responses. We conclude that T RM are sufficient to trigger rapid immune activation and recruitment in the CNS and may have an unappreciated role in driving neuroinflammation.
ABSTRACT
BACKGROUND: Establishing collaborations between cohort studies has been fundamental for progress in health research. However, such collaborations are hampered by heterogeneous data representations across cohorts and legal constraints to data sharing. The first arises from a lack of consensus in standards of data collection and representation across cohort studies and is usually tackled by applying data harmonization processes. The second is increasingly important due to raised awareness for privacy protection and stricter regulations, such as the GDPR. Federated learning has emerged as a privacy-preserving alternative to transferring data between institutions through analyzing data in a decentralized manner. METHODS: In this study, we set up a federated learning infrastructure for a consortium of nine Dutch cohorts with appropriate data available to the etiology of dementia, including an extract, transform, and load (ETL) pipeline for data harmonization. Additionally, we assessed the challenges of transforming and standardizing cohort data using the Observational Medical Outcomes Partnership (OMOP) common data model (CDM) and evaluated our tool in one of the cohorts employing federated algorithms. RESULTS: We successfully applied our ETL tool and observed a complete coverage of the cohorts' data by the OMOP CDM. The OMOP CDM facilitated the data representation and standardization, but we identified limitations for cohort-specific data fields and in the scope of the vocabularies available. Specific challenges arise in a multi-cohort federated collaboration due to technical constraints in local environments, data heterogeneity, and lack of direct access to the data. CONCLUSION: In this article, we describe the solutions to these challenges and limitations encountered in our study. Our study shows the potential of federated learning as a privacy-preserving solution for multi-cohort studies that enhance reproducibility and reuse of both data and analyses.
Subject(s)
Dementia , Humans , Netherlands , Cohort Studies , Algorithms , Information Dissemination/methods , Biomedical ResearchABSTRACT
The ecto-ATPase CD39 is expressed on exhausted CD8+ T cells in chronic viral infection and has been proposed as a marker of tumor-specific CD8+ T cells in cancer, but the role of CD39 in an effector and memory T cell response has not been clearly defined. We report that CD39 is expressed on antigen-specific CD8+ short-lived effector cells (SLECs), while it's co-ecto-enzyme, CD73, is found on memory precursor effector cells (MPEC) in vivo . Inhibition of CD39 enzymatic activity during in vitro T cell priming enhances MPEC differentiation in vivo after transfer and infection. The enriched MPEC phenotype is associated with enhanced tissue resident memory (T RM ) establishment in the brain and salivary gland following an acute intranasal viral infection, suggesting that CD39 ATPase activity plays a role in memory CD8+ T cell differentiation. We also show that CD39 is expressed on human and murine T RM across several non-lymphoid tissues and melanoma, while CD73 is expressed on both circulating and resident memory subsets in mice. In contrast to exhausted CD39+ T cells in chronic infection, CD39+ T RM are fully functional when stimulated ex vivo with cognate antigen. This work further expands the identity of CD39 beyond a T cell exhaustion marker.
ABSTRACT
Diminishing natural resources and increasing climatic volatility are impacting agri-food systems, prompting the need for sustainable and resilient alternatives. Python farming is well established in Asia but has received little attention from mainstream agricultural scientists. We measured growth rates in two species of large pythons (Malayopython reticulatus and Python bivittatus) in farms in Thailand and Vietnam and conducted feeding experiments to examine production efficiencies. Pythons grew rapidly over a 12-month period, and females grew faster than males. Food intake and growth rates early in life were strong predictors of total lifetime growth, with daily mass increments ranging from 0.24 to 19.7 g/day for M. reticulatus and 0.24 to 42.6 g/day for P. bivittatus, depending on food intake. Pythons that fasted for up to 4.2 months lost an average of 0.004% of their body mass per day, and resumed rapid growth as soon as feeding recommenced. Mean food conversion rate for dressed carcasses was 4.1%, with useable products (dressed carcass, skin, fat, gall bladder) comprising 82% of the mass of live animals. In terms of food and protein conversion ratios, pythons outperform all mainstream agricultural species studied to date. The ability of fasting pythons to regulate metabolic processes and maintain body condition enhances food security in volatile environments, suggesting that python farming may offer a flexible and efficient response to global food insecurity.
Subject(s)
Boidae , Animals , Female , Male , Boidae/physiology , Farms , Thailand , VietnamABSTRACT
PURPOSE: Arterial spin labeling (ASL) is a widely used contrast-free MRI method for assessing cerebral blood flow (CBF). Despite the generally adopted ASL acquisition guidelines, there is still wide variability in ASL analysis. We explored this variability through the ISMRM-OSIPI ASL-MRI Challenge, aiming to establish best practices for more reproducible ASL analysis. METHODS: Eight teams analyzed the challenge data, which included a high-resolution T1-weighted anatomical image and 10 pseudo-continuous ASL datasets simulated using a digital reference object to generate ground-truth CBF values in normal and pathological states. We compared the accuracy of CBF quantification from each team's analysis to the ground truth across all voxels and within predefined brain regions. Reproducibility of CBF across analysis pipelines was assessed using the intra-class correlation coefficient (ICC), limits of agreement (LOA), and replicability of generating similar CBF estimates from different processing approaches. RESULTS: Absolute errors in CBF estimates compared to ground-truth synthetic data ranged from 18.36 to 48.12 mL/100 g/min. Realistic motion incorporated into three datasets produced the largest absolute error and variability between teams, with the least agreement (ICC and LOA) with ground-truth results. Fifty percent of the submissions were replicated, and one produced three times larger CBF errors (46.59 mL/100 g/min) compared to submitted results. CONCLUSIONS: Variability in CBF measurements, influenced by differences in image processing, especially to compensate for motion, highlights the significance of standardizing ASL analysis workflows. We provide a recommendation for ASL processing based on top-performing approaches as a step toward ASL standardization.
Subject(s)
Brain , Cerebrovascular Circulation , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Spin Labels , Humans , Cerebrovascular Circulation/physiology , Reproducibility of Results , Brain/diagnostic imaging , Brain/blood supply , Image Processing, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Perfusion Imaging/methods , Male , Female , Adult , AlgorithmsABSTRACT
Moderate elevations of serum transaminases are frequently found in patients with diabetes mellitus and are attributed to fatty infiltration of the liver without further investigation. Recent studies of patients with end-stage liver disease have suggested a possible association between Herpatitis C virus (HCV) antibody positivity and the development of diabetes (mostly Type 2). As a first step in the examination of any potential association between HCV and type 2 diabetes in subjects without overt liver disease, we examined 200 British patient with Type 2 diabetes (100 White Caucasians, 50 Asians, and 50 Afro-Caribbeans), recruited from the United Kingdom Prospective Study of Diabetes, half of whom had a significant elevation of alanine aminotransferase (ALT) on at least two occasions and half of whom had consistently normal ALT levels. In Afro-Caribbean Type 2 diabetic subjects 7/25 (28 percent) patients with abnormal ALT and 1/25 (4 percent) with normal ALT were HCV antibody positive. Among White Caucasian subjects 6/50 (12 percent) patients with abnormal LFTs and 0/50 with normal LFTs were HCV antibody positive and in Asians the prevalence was 2/25 (8 percent) and 0/25, respectively. This study suggests that persistent mild to moderate elevation of serum transaminases in a patient with Type 2 diabetes should not automatically be attributed to the metabolic disturbances of diabetes. Particularly in Afro-Caribbean subjects, HCV infection is a major diagnostic consideration. The question of whether HCV infection itself may have a diabetogenic action is worthy of further investigation (AU)