The novel coronavirus SARS-CoV-2 continues to cause death and disease throughout the world, underscoring the necessity of understanding the virus and host immune response. From the start of the ...pandemic, a prominent pattern of central nervous system (CNS) pathologies, including demyelination, has emerged, suggesting an underlying mechanism of viral mimicry to CNS proteins. We hypothesized that immunodominant epitopes of SARS-CoV-2 share homology with proteins associated with multiple sclerosis (MS). Using PEPMatch, a newly developed bioinformatics package which predicts peptide similarity within specific amino acid mismatching parameters consistent with published MHC binding capacity, we discovered that nucleocapsid protein shares significant overlap with 22 MS-associated proteins, including myelin proteolipid protein (PLP). Further computational evaluation demonstrated that this overlap may have critical implications for T cell responses in MS patients and is likely unique to SARS-CoV-2 among the major human coronaviruses. Our findings substantiate the hypothesis of viral molecular mimicry in the pathogenesis of MS and warrant further experimental exploration.
When the body mounts an immune response against a foreign pathogen, the adaptive arm of the immune system relies upon clonal expansion of antigen-specific T cell populations to exercise acquired ...effector and cytotoxic functions to clear it. However, T cell expansion must be modulated to effectively combat the perceived threat without inducing excessive collateral damage to host tissues. Restimulation-induced cell death (RICD) is an apoptotic program triggered in activated T cells when an abundance of antigen and IL-2 are present, imposing a negative feedback mechanism that constrains the growing T cell population. This autoregulatory process can be detected via increases in caspase activation, Annexin V binding, and loss of mitochondrial membrane potential. However, simple changes in T cell viability through flow cytometric analysis can reliably measure RICD sensitivity in response to T-cell receptor (TCR) restimulation. This protocol describes the
polyclonal activation, expansion, and restimulation of human primary T cells isolated from donor peripheral blood mononuclear cells (PBMC). This simple procedure allows for accurate quantification of RICD via flow cytometry. We also describe strategies for interrogating the role of specific proteins and pathways that may alter RICD sensitivity. This straightforward protocol provides a quick and dependable tool to track RICD sensitivity in culture over time while probing critical factors that control the magnitude and longevity of an adaptive immune response. Graphic abstract:
simulation of restimulation-induced cell death in activated human T cells.
Immune homeostasis depends upon effective clearance of pathogens while simultaneously preventing autoimmunity and immunopathology in the host. Restimulation-induced cell death (RICD) is one such ...mechanism where by activated T cells receive subsequent antigenic stimulation, reach a critical signal threshold through the T cell receptor (TCR), and commit to apoptosis. Many details of this process remain unclear, including the role of co-stimulatory and co-inhibitory proteins that influence the TCR signaling cascade. Here we characterize the role of T cell immunoglobulin and mucin domain containing 3 (TIM-3) in RICD regulation. TIM-3 protected newly activated CD8
effector T cells from premature RICD during clonal expansion. Surprisingly, however, we found that TIM-3 potentiated RICD in late-stage effector T cells. The presence of TIM-3 increased proximal TCR signaling and proapoptotic protein expression in late-stage effector T cells, with no consistent signaling effects noted in newly activated cells with or without TIM-3. To better explain these differences in TIM-3 function as T cells aged, we characterized the temporal pattern of TIM-3 expression in effector T cells. We found that TIM-3 was expressed on the surface of newly activated effector T cells, but remained largely intracellular in late-stage effector cells. Consistent with this, TIM-3 required a ligand to prevent early RICD, whereas ligand manipulation had no effects at later stages. Of the known TIM-3 ligands, carcinoembryonic antigen-related cell adhesion molecule (CEACAM1) showed the greatest difference in surface expression over time and also protected newly activated cells from premature RICD, with no measurable effects in late-stage effectors. Indeed, CEACAM1 enabled TIM-3 surface expression on T cells, implying a co-dependency for these proteins in protecting expanding T cells from premature RICD. Our findings suggest that co-signaling proteins like TIM-3 and CEACAM1 can alter RICD sensitivity at different stages of the effector T cell response, with important implications for checkpoint blockade therapy.
Baylisascaris procyonis (raccoon roundworm) infection is common in raccoons and can cause devastating pathology in other animals, including humans. Limited information is available on the frequency ...of asymptomatic human infection. We tested 150 adults from California, USA, for B. procyonis antibodies; 11 were seropositive, suggesting that subclinical infection does occur.
For effective adaptive immunity, T lymphocytes must rapidly expand and contract in an antigen-specific manner to effectively control invading pathogens and preserve immunological memory, without ...sustaining excessive collateral damage to host tissues. Starting from initial antigen encounter, carefully calibrated programmed cell death pathways are critical for maintaining homeostasis over distinct phases of the T cell response. Restimulation-induced cell death (RICD), a self-regulatory apoptosis pathway triggered by re-engagement of the T cell receptor (TCR), is particularly important for constraining effector T cell expansion to preclude overt immunopathology; indeed, genetic disorders affecting key molecules involved in RICD execution can manifest in excessive lymphoproliferation, malignancy, and autoimmunity. Herein we review our current knowledge of how RICD sensitivity is ultimately regulated over the course of an immune response, including recent revelations on molecules that tune RICD by enforcing resistance or promoting susceptibility in expanding versus mature effector T cells, respectively. Detailed dissection of the molecular and temporal control of RICD also illuminates novel therapeutic strategies for correcting abnormal T cell responses noted in various immune disorders by ultimately tuning RICD sensitivity.
Abstract Objectives Public sharing of de-identified biomedical data promotes collaboration between researchers and accelerates the development of disease prevention and treatment strategies. However, ...open-access data sharing presents challenges to researchers who need to protect the privacy of study participants, ensure that data are used appropriately, and acknowledge the inputs of all involved researchers. This article presents an approach to data sharing which addresses the above challenges by using a publicly available dashboard with de-identified, aggregated participant data from a large HIV surveillance cohort. Materials and Methods Data in this study originated from the Rakai Community Cohort Study (RCCS), which was integrated into a centralized data mart as part of a larger data management strategy for the Rakai Health Sciences Program in Uganda. These data were used to build a publicly available, protected health information (PHI)-secured visualization dashboard for general research use. Results Using two unique case studies, we demonstrate the capability of the dashboard to generate the following hypotheses: firstly, that HIV prevention strategies ART and circumcision have differing levels of impact depending on the marital status of investigated communities; secondly, that ART is very successful in comparison to circumcision as an interventional strategy in certain communities. Discussion The democratization of large-scale anonymized epidemiological data using public-facing dashboards has multiple benefits, including facilitated exploration of research data and increased reproducibility of research findings. Conclusion By allowing the public to explore data in depth and form new hypotheses, public-facing dashboard platforms have significant potential to generate new relationships and collaborations and further scientific discovery and reproducibility.
Background
Over 86% of American Indian and Alaska Native elders live in urban metropolitan areas, yet the extant epidemiological data on cognition and aging in this racial and ethnic population has ...been collected in reservation communities and may have limited generalizability to the larger population. Multi‐faceted, high quality data are needed to assess risk and protective factors in this underserved and understudied population.
Method
We intend to collect medical history, lifestyle and behavioral history, neurocognitive battery, anthropometric measures, blood and urine samples, cranial 3T MRI, rsfMRI, and wrist actigraphy data from 1200 urban‐dwelling Native elders (age 55 and older) across 5 major metropolitan areas: Anchorage, AK; Seattle, WA; San Bernardino, CA; Phoenix, AZ; and Oklahoma City, OK. This initial cohort will be the first in a NIA‐funded longitudinal cohort study to evaluate the brain and cognitive health of this population as they advance in age.
Result
Originally funded in the summer of 2019, data collection was initially delayed due to the pandemic, but was initiated at one site (Phoenix) in the summer of 2021 and is now underway at all 5 field sites, with a total of 260 participants enrolled as of the time of this writing.
Conclusion
This study represents the largest effort to characterize the cognition and brain health of a generalizable sample of urban‐dwelling American Indian and Alaska Native elders to date.
The adaptive immune response relies on specific apoptotic programs to maintain homeostasis. Conventional effector T cell (Tcon) expansion is constrained by both forkhead box P3 (FOXP3)
-regulatory T ...cells (Tregs) and restimulation-induced cell death (RICD), a propriocidal apoptosis pathway triggered by repeated stimulation through the T-cell receptor (TCR). Constitutive FOXP3 expression protects Tregs from RICD by suppressing SLAM-associated protein (SAP), a key adaptor protein that amplifies TCR signaling strength. The role of transient FOXP3 induction in activated human CD4 and CD8 Tcons remains unresolved, but its expression is inversely correlated with acquired RICD sensitivity. Here, we describe a novel role for FOXP3 in protecting human Tcons from premature RICD during expansion. Unlike FOXP3-mediated protection from RICD in Tregs, FOXP3 protects Tcons through a distinct mechanism requiring de novo transcription that does not require SAP suppression. Transcriptome profiling and functional analyses of expanding Tcons revealed that FOXP3 enhances expression of the SLAM family receptor CD48, which in turn sustains basal autophagy and suppresses pro-apoptotic p53 signaling. Both CD48 and FOXP3 expression reduced p53 accumulation upon TCR restimulation. Furthermore, silencing FOXP3 expression or blocking CD48 decreased the mitochondrial membrane potential in expanding Tcons with a concomitant reduction in basal autophagy. Our findings suggest that FOXP3 governs a distinct transcriptional program in early-stage effector Tcons that maintains RICD resistance via CD48-dependent protective autophagy and p53 suppression.
Highlights • Brominated flame retardants (BFR) are associated with neurobehavioral deficits • HBCDD exposure decreased presynaptic dopaminergic proteins in the hippocampus • Postsynaptic dopaminergic ...proteins in the hippocampus were not changed • This suggests the hippocampal dopamine circuit is vulnerable to HBCDD • Alterations to this circuit by HBCDD may underlie learning and memory deficits
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