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New role for white blood cells in the developing brain

Key points:

• Researchers based at the �鶹��Ƶ and at VIB-KU Leuven in Belgium have undertaken an in-depth study of a specialised brain-resident population of immune cells to understand their role in brain development.
• The presence of these cells in the brain is essential for normal brain development in mice.
• The research, led by Professor Adrian Liston, indicates an important role for CD4 T cells in the maturation of microglia, and in acting as important ‘go-betweens’ to convey information between the body and the brain.

Whether white blood cells can be found in the brain has been controversial, and their role there a complete mystery. In a study published in Cell, an international team of scientists led by Professor Adrian Liston (Babraham �鶹��Ƶ, UK &  VIB-KU Leuven, Belgium) describe a population of specialised brain-resident immune cells discovered in the mouse and human brain, and show that the presence of white blood cells is essential for normal brain development in mice.

Like a highly fortified headquarters, our brain enjoys special protection from what is circulating in the rest of our body through the blood-brain barrier. This highly selective border makes sure that passage from the blood to the brain is tightly regulated.

The blood-brain barrier also separates the brain from our body’s immune system, which is why it has its own resident immune cells, called microglia, which trigger inflammation and tissue repair. Microglia arrive in the brain during embryonic development, and later on, the population becomes self-renewing.

Yet, white blood cells—which are part of our immune system—have been found to play a role in different brain diseases, including multiple sclerosis, Alzheimer’s and Parkinson’s disease or stroke. Whether or not white blood cells can be found in healthy brains as well, and what they might be doing there, has been subject of intense debate. An interdisciplinary team of scientists led by Prof. Adrian Liston (Babraham �鶹��Ƶ and VIB-KU Leuven) set out to find the answers.

White blood cells in the brain
"A misconception about white blood cells comes from their name,” explains Dr Oliver Burton (Babraham �鶹��Ƶ). “These 'immune cells' are not just present in the blood. They are constantly circulating around our body and enter all of our organs, including—as it turns out—the brain. We are only just starting to discover what white blood cells do when they leave the blood. This research indicates that they act as a go-between, transferring information from the rest of the body to the brain environment."

The team quantified and characterised a small but distinct population of brain-resident T helper cells present in mouse and human brain tissue. T cells are a specific type of white blood cells specialised for scanning cell surfaces for evidence of infection and triggering an appropriate immune response. New technologies allowed the researchers to study the cells in great detail, including the processes by which circulating T cells entered the brain and began to develop the features of brain-resident T cells.

Dr Carlos Roca (Babraham �鶹��Ƶ): “Science is becoming increasingly multidisciplinary. Here, we didn't just bring in expertise from immunology, neuroscience and microbiology, but also from computer science and applied mathematics. New approaches for data analysis allow us to reach a much deeper level of understanding of the biology of the white blood cells we found in the brain.”

An evolutionary role
When T helper cells are absent from the brain, the scientists found that the resident immune cells – microglia – in the mouse brain remained suspended between a fetal and adult developmental state. Observationally, mice lacking brain T cells showed multiple changes in their behavior. The analysis points to an important role for brain-resident T cells in brain development. If T cells participate in normal brain development in mice, could the same be true in humans?

“In mice, the wave of entry of immune cells at birth triggers a switch in brain development,” says Liston. “Humans have a much longer gestation than mice though, and we don't know about the timing of immune cell entry into the brain. Does this occur before birth? Is it delayed until after birth? Did a change in timing of entry contribute to the evolution of enhanced cognitive capacity in humans?”

The findings open up a whole new range of questions about how the brain and our immune system interact. "It has been really exciting to work on this project. We are learning so much about how our immune system can alter our brain, and how our brain modifies our immune system. The two are far more interconnected than we previously thought," says Dr Emanuela Pasciuto (VIB-KU Leuven).

The study also brings in a connection with the gut microbiome, says Liston: “There are now multiple links between the bacteria in our gut and different neurological conditions, but without any convincing explanations for what connects them. We show that white blood cells are modified by gut bacteria, and then take that information with them into the brain. This could be the route by which our gut microbiome influences the brain.” 

Taken together, the results contribute towards the increasing recognition of the role of immune cells in the brain and shed new light on its involvement in a range of neurological diseases.

Watch the video summary (narrated by Adrian Liston)

Notes to Editors

Publication reference
Pasciuto, Burton, Roca et al.
Microglia require CD4 T cells to complete the fetal to adult transition.
Cell
DOI: 10.1016/j.cell.2020.06.026

Press contacts:
Adrian Liston, Senior Group Leader, Babraham �鶹��Ƶ, UK and VIB-KU Leuven, Belgium
Mobile: +44 (0)7444 620331 Mail:  adrian.liston@babraham.ac.uk 

Louisa Wood, Communications Manager, Babraham �鶹��Ƶ
Mobile:  M: +44 (0)7833 481170
Mail: louisa.wood@babraham.ac.uk

Image description
A murine T cell (green), having migrated from the blood (red) interacts with maturing microglia (white) in the midbrain. Image credit: James Dooley, Babraham �鶹��Ƶ.

Affiliated authors (in author order):
Dr Oliver Burton, senior postdoctoral researcher, Liston lab
Dr Carlos Roca, postdoctoral researcher, Liston lab
Dr Carly Whyte, visiting scientist,
Dr James Dooley, senior staff scientist, Liston lab
Professor Adrian Liston, senior group leader, Immunology research programme

Research funding
This work was supported by the VIB, the KUL, the Rega �鶹��Ƶ, the ERC Consolidator Grant TissueTreg (to Adrian Liston), the ERC Advanced Grant CellPhase AD (to Bart De Strooper) and the Biotechnology and Biological Sciences Research Council through �鶹��Ƶ Strategic Program Grant funding and a Core Capability Grant to �鶹��Ƶ.

Additional/related resources
News, 10 January 2020 EU grant success to harness the immune system to treat brain damage

Animal research statement
As a publicly funded research institute, �鶹��Ƶ is committed to engagement and transparency in all aspects of its research. The research presented here used both human brain samples and mice. Mice were used to study the effects of CD4 T cell depletion, in joining (parabiosis) experiments to fuse the circulatory systems of two mice and in behavioural studies. Experiments were performed in accordance with the local overseeing authority, depending on where they were undertaken. This involved review of the locally-undertaken procedures by the University of Leuven Animal Ethics Committee, �鶹��Ƶ Animal Welfare and Ethics Review Body, the University of Belfast Animal Welfare and Ethics Review Body and CEAAToulouse (Comités d'éthique en expérimentation animale). Animal husbandry and experimentation complied with existing European Union and national legislation and local standards.

Please follow the link for further details of our animal research and our animal welfare practices.

Babraham �鶹��Ƶ
�鶹��Ƶ undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation, immunology and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The �鶹��Ƶ is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through �鶹��Ƶ Strategic Programme Grants and an �鶹��Ƶ Core Capability Grant, and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.

BBSRC (strategic funder of �鶹��Ƶ)
The Biotechnology and Biological Sciences Research Council (BBSRC) is part of UK Research and Innovation, a non-departmental public body funded by a grant-in-aid from the UK government. BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

Funded by government, BBSRC invested £451 million in world-class bioscience in 2019-20. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.

VIB-KU Leuven Center for Brain & Disease Research
Scientists at the VIB-KU Leuven Center for Brain & Disease study how brain cells are organized and how they communicate with each other. These mechanisms reveal and provide insights into what goes wrong in brain diseases such as Alzheimer's, Parkinson's, ALS and dystonia. This basic work should ultimately lead to new drugs for use against these currently incurable diseases.

VIB
Basic research in life sciences is VIB’s raison d’être. VIB is an independent research institute where some 1,500 top scientists from Belgium and abroad conduct pioneering basic research. As such, they are pushing the boundaries of what we know about molecular mechanisms and how they rule living organisms such as human beings, animals, plants and microorganisms. Based on a close partnership with five Flemish universities – Ghent University, KU Leuven, University of Antwerp, Vrije Universiteit Brussel and Hasselt University – and supported by a solid funding program, VIB unites the expertise of all its collaborators and research groups in a single institute. VIB’s technology transfer activities translate research results into concrete benefits for society such as new diagnostics and therapies and agricultural innovations. These applications are often developed by young start-ups from VIB or through collaborations with other companies. This also leads to additional employment and bridges the gap between scientific research and entrepreneurship. VIB also engages actively in the public debate on biotechnology by developing and disseminating a wide range of science-based information. More info can be found on .

KU Leuven
KU Leuven is a leading European university dedicated to research, education and service to society. It is a founding member of the League of European Research Universities (LERU) and has a strong European and international orientation. Its sizeable academic staff conducts basic and applied research in a comprehensive range of disciplines. University Hospitals Leuven, its network of research hospitals, provides high-quality healthcare and develops new therapeutic and diagnostic insights with an emphasis on translational research. The University welcomes more 50,000 students from over 140 countries. Its doctoral schools organise internationally oriented PhD programmes for over 4,500 doctoral students. More info: .