Immunology meets single-cell sequencing

A new computational approach in single-cell genomics reveals how different types of T cells detect, destroy and remember invaders.

Research from the Single-Cell Genomics Centre on the Wellcome Genome Campus could change the way we look at gene expression and immune response. Published in Nature Methods, the new method, TraCeR, provides a powerful tool for research into immune response, vaccination, cancer and autoimmunity.

What makes one T cell attack an antigen, and another remember it for next time? A series of RNA sequencing experiments by the Teichmann group at the European Bioinformatics Institute (EMBL-EBI) and the Wellcome Trust Sanger Institute led the group to develop a new technique for understanding T-cell receptors. TraCeR, a single-cell sequencing tool, allows the determination of both the sequence of the T-cell receptor in individual cells, along with each cell’s gene expression profile. This opens up new possibilities in the future for developing rapid diagnostics based on the genetic profile of blood cells.

When your immune system detects an invader – whether that’s a disease or, in the case of autoimmune disease, part of your own body – it starts producing an army of T cells to remove the pathogen, which itself is producing lots of different proteins.

“It’s a battlefield, with fighters on different fronts, snipers, generals and even journalists bearing witness. What we wanted to know was how different populations of T cells respond to disease – what role they’re playing in the battle.”

Mike Stubbington at the Sanger Institute and previously at EMBL-EBI

T cells are equipped with receptors that can latch on to a particular invader out of a vast array of possible options. This means they are extremely variable, with hundreds of billions of possible DNA sequences. A combination of paired sequences determines what protein a receptor will detect, so to understand what is happening at the molecular level, it is imperative to find both sequences in each cell. Using TraCeR, scientists can look at the DNA and RNA (expression) profiles of these highly variable T-cell receptors at the same time.

The researchers found the receptor sequences are unique, unless the T cells have the same parent cell. The presence of ‘sibling’ cells proves that an infection has triggered the division of a particular T cell, which indicates it is multiplying to fight the invader. Using TraCeR, the researchers accurately identified ‘sibling’ cells and explored their different response to Salmonella infection.

“This technique helps us see whether all the ‘children’ of a particular T cell do the same thing at the same time, which is an open question in biology. We can start to see whether the antigen itself plays a role in how a T cell will respond, and even whether it’s possible to determine what the invader is, just based on the sequence of a T-cell receptor.”

Tapio Lönnberg of EMBL-EBI

“This kind of breakthrough work can only be done using single-cell measurements. This new tool for single-cell sequencing gives us a new approach to the study of T cells And opens up new opportunities to explore immune responses in disease, vaccination, cancer and autoimmunity.”

Sarah Teichmann, Head of Cellular Genetics at the Sanger Institute

The next step for the team is to apply similar methods to the study of B cells to better understand the adaptive immune system as a whole.

More information

Funding

This research was supported by the European Research Council and the Lister Institute for Preventative Medicine.

Participating Centres

  • European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK
  • Wellcome Trust Sanger Institute, Cambridge, UK

Publications:

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Selected websites

  • The Sanger/EMBL-EBI Single Cell Genomics Centre

    The aim of the Sanger Institute/EMBL-EBI Single-Cell Genomics Centre is to develop and apply methods for capturing the complete genetic content of single cells in a high-throughput manner, enabling the exploration of cellular heterogeneity in normal development and disease. In addition to wet-lab approaches, we also develop the computational means for the analysis of single cells.

  • EMBL

    EMBL is Europe’s flagship laboratory for the life sciences, with more than 80 independent groups covering the spectrum of molecular biology. EMBL is international, innovative and interdisciplinary – its 1800 employees, from many nations, operate across five sites: the main laboratory in Heidelberg, and outstations in Grenoble; Hamburg; Hinxton, near Cambridge (the European Bioinformatics Institute), and Monterotondo, near Rome. Founded in 1974, EMBL is an inter-governmental organisation funded by public research monies from its member states. The cornerstones of EMBL’s mission are: to perform basic research in molecular biology; to train scientists, students and visitors at all levels; to offer vital services to scientists in the member states; to develop new instruments and methods in the life sciences and actively engage in technology transfer activities, and to integrate European life science research. Around 200 students are enrolled in EMBL’s International PhD programme. Additionally, the Laboratory offers a platform for dialogue with the general public through various science communication activities such as lecture series, visitor programmes and the dissemination of scientific achievements.

  • EMBL-EBI

    The European Bioinformatics Institute is part of EMBL, and is a global leader in the storage, analysis and dissemination of large biological datasets. EMBL-EBI helps scientists realise the potential of ‘big data’ by enhancing their ability to exploit complex information to make discoveries that benefit mankind. We are a non-profit, intergovernmental organisation funded by EMBL’s 21 member states and two associate member states. Our 570 staff hail from 57 countries, and we welcome a regular stream of visiting scientists throughout the year. We are located on the Wellcome Genome Campus in Hinxton, Cambridge in the United Kingdom.

  • The Wellcome Trust Sanger Institute

    The Wellcome Trust Sanger Institute is one of the world’s leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.

  • The Wellcome Trust

    The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.