A tissue-like platform for studying engineered quiescent human T-cells' interactions with dendritic cells
- University of Oxford, United Kingdom
Abstract
Research in the field of human immunology is restricted by the lack of a system that reconstitutes the in-situ activation dynamics of quiescent human antigen-specific T-cells interacting with dendritic cells. Here we report a tissue-like system that recapitulates the dynamics of engineered primary human immune cell. Our approach facilitates real-time single cell manipulations, tracking of interactions and functional responses complemented by population-based measurements of cytokines, activation status and proliferation. As a proof of concept, we recapitulate immunological phenomenon such as CD4 help to CD8 T-cells through enhanced maturation of DCs and effect of PD-1 checkpoint blockades. In addition, we characterise unique dynamics of T-cell/DC interactions as a function of antigen affinity.
Data availability
No new gene datasets were generated during this study. Source data files have been provided for Figures 2, 3, and 4. The TCR sequences used have been published in the past in the literature (cited in the manuscript) and the modifications made are clearly stated in the tables in the manuscript. The constructs are available through a request to the corresponding authors of the previously published articles.
Article and author information
Author details
Funding
Wellcome Trust (100262Z/12/Z)
- Michael L Dustin
Wellcome Trust (207537/Z/17/Z)
- Omer Dushek
European Research Council (ERC-2014-AdG_670930)
- Štefan Bálint
- Viveka Mayya
Human Frontier Science Program (RGP0033/2015)
- Michael L Dustin
UCB-Oxford
- Enas Abu Shah
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: This project has been approved by the Medical Sciences Inter-Divisional Research Ethics Committee of the University of Oxford REC 11/H0711/7 to cover the use of human blood products purchased from National Health Services Blood and Transplant service (NHS England).
Copyright
© 2019, Abu Shah et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A tissue-like platform for studying engineered quiescent human T-cells' interactions with dendritic cells
eLife 8:e48221.
https://doi.org/10.7554/eLife.48221
Further reading
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- Immunology and Inflammation
- Medicine
Background:
Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display clear signs of immune dysregulation, including high rates of autoimmunity and severe complications from infections. Although it is well established that T21 causes increased interferon responses and JAK/STAT signaling, elevated autoantibodies, global immune remodeling, and hypercytokinemia, the interplay between these processes, the clinical manifestations of DS, and potential therapeutic interventions remain ill defined.
Methods:
We report a comprehensive analysis of immune dysregulation at the clinical, cellular, and molecular level in hundreds of individuals with DS, including autoantibody profiling, cytokine analysis, and deep immune mapping. We also report the interim analysis of a Phase II clinical trial investigating the safety and efficacy of the JAK inhibitor tofacitinib through multiple clinical and molecular endpoints.
Results:
We demonstrate multi-organ autoimmunity of pediatric onset concurrent with unexpected autoantibody-phenotype associations in DS. Importantly, constitutive immune remodeling and hypercytokinemia occur from an early age prior to autoimmune diagnoses or autoantibody production. Analysis of the first 10 participants to complete 16 weeks of tofacitinib treatment shows a good safety profile and no serious adverse events. Treatment reduced skin pathology in alopecia areata, psoriasis, and atopic dermatitis, while decreasing interferon scores, cytokine scores, and levels of pathogenic autoantibodies without overt immune suppression.
Conclusions:
JAK inhibition is a valid strategy to treat autoimmune conditions in DS. Additional research is needed to define the effects of JAK inhibition on the broader developmental and clinical hallmarks of DS.
Funding:
NIAMS, Global Down Syndrome Foundation.
Clinical trial number:
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- Immunology and Inflammation
- Medicine
Metabolic abnormalities associated with liver disease have a significant impact on the risk and prognosis of cholecystitis. However, the underlying mechanism remains to be elucidated. Here, we investigated this issue using Wilson’s disease (WD) as a model, which is a genetic disorder characterized by impaired mitochondrial function and copper metabolism. Our retrospective clinical study found that WD patients have a significantly higher incidence of cholecystitis and a poorer prognosis. The hepatic immune cell landscape using single-cell RNA sequencing showed that the tissue immune microenvironment is altered in WD, mainly a major change in the constitution and function of the innate immune system. Exhaustion of natural killer (NK) cells is the fundamental factor, supported by the upregulated expression of inhibitory receptors and the downregulated expression of cytotoxic molecules, which was verified in clinical samples. Further bioinformatic analysis confirmed a positive correlation between NK cell exhaustion and poor prognosis in cholecystitis and other inflammatory diseases. The study demonstrated dysfunction of liver immune cells triggered by specific metabolic abnormalities in WD, with a focus on the correlation between NK cell exhaustion and poor healing of cholecystitis, providing new insights into the improvement of inflammatory diseases by assessing immune cell function.
