Life Sciences Research for Lifelong Health

Adrian Liston

Research Summary

The Liston laboratory works on regulatory T cells. These are a type of white blood cell that act to suppress the rest of the immune response, preventing spontaneous autoimmune disease and acting as a rheostat to control just how active our immune system is. The number of these cells in our blood goes up as we get old, which may contribute to the immune-supressed state of older persons. We seek to understand these cells, using both patient material and mouse models, so that we can harness their power to fine-tune the immune system for healthy ageing.

We are currently advertising for a PhD Studentship entitled 'Using the immune system to cure traumatic brain injury' - more details are available at: www.babraham.ac.uk/vacancies-training/phd-programme/phd-opportunities

Latest Publications

Stem-cell-derived human microglia transplanted in mouse brain to study human disease.
Mancuso R, Van Den Daele J, Fattorelli N, Wolfs L, Balusu S, Burton O, Liston A, Sierksma A, Fourne Y, Poovathingal S, Arranz-Mendiguren A, Sala Frigerio C, Claes C, Serneels L, Theys T, Perry VH, Verfaillie C, Fiers M, De Strooper B

Although genetics highlights the role of microglia in Alzheimer's disease, one-third of putative Alzheimer's disease risk genes lack adequate mouse orthologs. Here we successfully engraft human microglia derived from embryonic stem cells in the mouse brain. The cells recapitulate transcriptionally human primary microglia ex vivo and show expression of human-specific Alzheimer's disease risk genes. Oligomeric amyloid-β induces a divergent response in human versus mouse microglia. This model can be used to study the role of microglia in neurological diseases.

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Nature neuroscience, , 1546-1726, , 2019

PMID: 31659342

Longitudinal In Vivo Assessment of Host-Microbe Interactions in a Murine Model of Pulmonary Aspergillosis.
Saini S, Poelmans J, Korf H, Dooley JL, Liang S, Manshian BB, Verbeke R, Soenen SJ, Vande Velde G, Lentacker I, Lagrou K, Liston A, Gysemans C, De Smedt SC, Himmelreich U

The fungus Aspergillus fumigatus is ubiquitous in nature and the most common cause of invasive pulmonary aspergillosis (IPA) in patients with a compromised immune system. The development of IPA in patients under immunosuppressive treatment or in patients with primary immunodeficiency demonstrates the importance of the host immune response in controlling aspergillosis. However, study of the host-microbe interaction has been hampered by the lack of tools for their non-invasive assessment. We developed a methodology to study the response of the host's immune system against IPA longitudinally in vivo by using fluorine-19 magnetic resonance imaging (F MRI). We showed the advantage of a perfluorocarbon-based contrast agent for the in vivo labeling of macrophages and dendritic cells, permitting quantification of pulmonary inflammation in different murine IPA models. Our findings reveal the potential of F MRI for the assessment of rapid kinetics of innate immune response against IPA and the permissive niche generated through immunosuppression.

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iScience, 20, 2589-0042, 184-194, 2019

PMID: 31581067

Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition.
Habets RA, de Bock CE, Serneels L, Lodewijckx I, Verbeke D, Nittner D, Narlawar R, Demeyer S, Dooley J, Liston A, Taghon T, Cools J, de Strooper B

Given the high frequency of activating mutations in T cell acute lymphoblastic leukemia (T-ALL), inhibition of the γ-secretase complex remains an attractive target to prevent ligand-independent release of the cytoplasmic tail and oncogenic NOTCH1 signaling. However, four different γ-secretase complexes exist, and available inhibitors block all complexes equally. As a result, these cause severe "on-target" gastrointestinal tract, skin, and thymus toxicity, limiting their therapeutic application. Here, we demonstrate that genetic deletion or pharmacologic inhibition of the presenilin-1 (PSEN1) subclass of γ-secretase complexes is highly effective in decreasing leukemia while avoiding dose-limiting toxicities. Clinically, T-ALL samples were found to selectively express only PSEN1-containing γ-secretase complexes. The conditional knockout of in developing T cells attenuated the development of a mutant NOTCH1-driven leukemia in mice in vivo but did not abrogate normal T cell development. Treatment of T-ALL cell lines with the selective PSEN1 inhibitor MRK-560 effectively decreased mutant NOTCH1 processing and led to cell cycle arrest. These observations were extended to T-ALL patient-derived xenografts in vivo, demonstrating that MRK-560 treatment decreases leukemia burden and increased overall survival without any associated gut toxicity. Therefore, PSEN1-selective compounds provide a potential therapeutic strategy for safe and effective targeting of T-ALL and possibly also for other diseases in which NOTCH signaling plays a role.

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Science translational medicine, 11, 1946-6242, , 2019

PMID: 31142678

Group Members

Latest Publications

Stem-cell-derived human microglia transplanted in mouse brain to study human disease.

Mancuso R, Van Den Daele J, Fattorelli N

Nature neuroscience
1546-1726: (2019)

PMID: 31659342

Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition.

Habets RA, de Bock CE, Serneels L

Science translational medicine
11 1946-6242: (2019)

PMID: 31142678

Inborn errors of immunity: single mutations unravel mechanisms of immune disease.

Liston A, Humblet-Baron S

Immunology and cell biology
1440-1711: (2019)

PMID: 30942931

The Aire family expands.

Liston A, Dooley J

The Journal of experimental medicine
1540-9538: (2019)

PMID: 30923044

Machine learning identifies an immunological pattern associated with multiple juvenile idiopathic arthritis subtypes.

Van Nieuwenhove E, Lagou V, Van Eyck L

Annals of the rheumatic diseases
1468-2060: (2019)

PMID: 30862608

Prospective study evaluating immune-mediated mechanisms and predisposing factors underlying persistent postinfectious abdominal complaints.

Florens MV, Van Wanrooy S, Dooley J

Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society
31 1365-2982:e13542 (2019)

PMID: 30657233

IFN-γ and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis.

Humblet-Baron S, Franckaert D, Dooley J

The Journal of allergy and clinical immunology
1097-6825: (2018)

PMID: 30578871

NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology.

Schlenner S, Pasciuto E, Lagou V

Annals of the rheumatic diseases
78 1468-2060:342-349 (2019)

PMID: 30552177

Genetic Architecture of Adaptive Immune System Identifies Key Immune Regulators.

Lagou V, Garcia-Perez JE, Smets I

Cell reports
25 2211-1247:798-810.e6 (2018)

PMID: 30332657