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.

Latest Publications

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

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

T cell tolerance depends upon Aire-expressing cells to purge the T cell repertoire of autoreactive clones. Once thought to be the exclusive domain of thymic epithelial cells, a new study by Yamano et al. (https://doi.org/10.1084/jem.20181430) in this issue of identifies ILC3-like cells in the lymph nodes with similar properties.

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The Journal of experimental medicine, , 1540-9538, , 2019

PMID: 30923044

Group Members

Latest Publications

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

Mice Deficient in Nucleoporin Nup210 Develop Peripheral T Cell Alterations.

van Nieuwenhuijze A, Burton O, Lemaitre P

Frontiers in immunology
9 1664-3224:2234 (2018)

PMID: 30323813

The Long Non-coding RNA Anticipates Foxp3 Expression in Regulatory T Cells.

Brajic A, Franckaert D, Burton O

Frontiers in immunology
9 1664-3224:1989 (2018)

PMID: 30319599