Cytotoxic T lymphocytes (CTLs) are thought to arrive at target sites either via random search or following signals by other leukocytes. Here, we reveal independent emergent behaviour in CTL populations attacking tumour masses. Primary murine CTLs coordinate their migration in a process reminiscent of the swarming observed in neutrophils. CTLs engaging cognate targets accelerate the recruitment of distant T cells through long-range homotypic signalling, in part mediated via the diffusion of chemokines CCL3 and CCL4. Newly arriving CTLs augment the chemotactic signal, further accelerating mass recruitment in a positive feedback loop. Activated effector human T cells and chimeric antigen receptor (CAR) T cells similarly employ intra-population signalling to drive rapid convergence. Thus, CTLs recognising a cognate target can induce a localised mass response by amplifying the direct recruitment of additional T cells independently of other leukocytes.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files with extensive statistical information have been provided for all figures containing bar, box or violin plots. Complete transcriptomics and secretomics data are available in Supplementary Files 1 and 2 respectively. Custom code and notes are available at http://www.matebiro.com/software/motilisim
- Gregory Rice
- David R Nisbet
- Mark N Read
- Maté Biro
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All animal breeding and experimentation were conducted in accordance with New South Wales state and Australian federal laws and animal ethics protocols overseen and approved by the University of New South Wales Animal Care and Ethics Committee (ACEC) under protocols 16/83B and 19/133B.
Human subjects: Human peripheral blood mononuclear cells (PBMCs) were obtained from healthy donors after informed consent and were used in experiments under a Human Research Ethics Committee (HREC) approved protocol (Sydney Children's Hospitals Network, LNR/13/SCHN/241).
- Satyajit Rath, Indian Institute of Science Education and Research (IISER), India
© 2020, Galeano Niño 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.
The muscle synergy is a guiding concept in motor control research that relies on the general notion of muscles ‘working together’ towards task performance. However, although the synergy concept has provided valuable insights into motor coordination, muscle interactions have not been fully characterised with respect to task performance. Here, we address this research gap by proposing a novel perspective to the muscle synergy that assigns specific functional roles to muscle couplings by characterising their task-relevance. Our novel perspective provides nuance to the muscle synergy concept, demonstrating how muscular interactions can ‘work together’ in different ways: (1) irrespective of the task at hand but also (2) redundantly or (3) complementarily towards common task-goals. To establish this perspective, we leverage information- and network-theory and dimensionality reduction methods to include discrete and continuous task parameters directly during muscle synergy extraction. Specifically, we introduce co-information as a measure of the task-relevance of muscle interactions and use it to categorise such interactions as task-irrelevant (present across tasks), redundant (shared task information), or synergistic (different task information). To demonstrate these types of interactions in real data, we firstly apply the framework in a simple way, revealing its added functional and physiological relevance with respect to current approaches. We then apply the framework to large-scale datasets and extract generalizable and scale-invariant representations consisting of subnetworks of synchronised muscle couplings and distinct temporal patterns. The representations effectively capture the functional interplay between task end-goals and biomechanical affordances and the concurrent processing of functionally similar and complementary task information. The proposed framework unifies the capabilities of current approaches in capturing distinct motor features while providing novel insights and research opportunities through a nuanced perspective to the muscle synergy.
Cell-free DNA (cfDNA) tests use small amounts of DNA in the bloodstream as biomarkers. While it is thought that cfDNA is largely released by dying cells, the proportion of dying cells' DNA that reaches the bloodstream is unknown. Here, we integrate estimates of cellular turnover rates to calculate the expected amount of cfDNA. By comparing this to the actual amount of cell type-specific cfDNA, we estimate the proportion of DNA reaching plasma as cfDNA. We demonstrate that <10% of the DNA from dying cells is detectable in plasma, and the ratios of measured to expected cfDNA levels vary a thousand-fold among cell types, often reaching well below 0.1%. The analysis suggests that local clearance, presumably via phagocytosis, takes up most of the dying cells' DNA. Insights into the underlying mechanism may help to understand the physiological significance of cfDNA and improve the sensitivity of liquid biopsies.