Sophie Rouvray

University of Birmingham

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David A.J. Lecky

University of Birmingham

David Bending

University of Birmingham

Lozan Sheriff

University of Birmingham

Rebecca A. Drummond

University of Birmingham

Thomas A.E. Elliot

University of Birmingham

L. George

University of Birmingham

Emma Jennings

Mallow General Hospital

Kendle M. Maslowski

University of Birmingham

David C. Wraith

University of Birmingham

Gillian M. Mackie

University of Birmingham

Cooperative Institutions

University of Birmingham

Institute of Immunology

Imperial College London

Cancer Research UK

University Hospitals Birmingham NHS Foundation Trust

Queen Elizabeth Hospital

National Institute for Health Research

NIHR Birmingham Biomedical Research Centre

The London College

University College London

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Nur77-Tempo mice reveal T cell steady state antigen recognition

Discovery Immunology (2022)

Thomas A.E. Elliot Emma Jennings David A.J. Lecky Sophie Rouvray Gillian M. Mackie

Abstract In lymphocytes, Nr4a gene expression is specifically regulated by antigen receptor signalling, making them ideal targets for use as distal T cell receptor (TCR) reporters. Nr4a3-Timer of cell kinetics and activity (Tocky) mice are a ground-breaking tool to report TCR-driven Nr4a3 expression using Fluorescent Timer protein (FT). FT undergoes a time-dependent shift in its emission spectrum following translation, allowing for the temporal reporting of transcriptional events. Our recent work suggested that Nr4a1/Nur77 may be a more sensitive gene to distal TCR signals compared to Nr4a3, so we, therefore, generated Nur77-Timer-rapidly-expressed-in-lymphocytes (Tempo) mice that express FT under the regulation of Nur77. We validated the ability of Nur77-Tempo mice to report TCR and B cell receptor signals and investigated the signals regulating Nur77-FT expression. We found that Nur77-FT was sensitive to low-strength TCR signals, and its brightness was graded in response to TCR signal strength. Nur77-FT detected positive selection signals in the thymus, and analysis of FT expression revealed that positive selection signals are often persistent in nature, with most thymic Treg expressing FT Blue. We found that active TCR signals in the spleen are low frequency, but CD69+ lymphoid T cells are enriched for FT Blue+ Red+ T cells, suggesting frequent TCR signalling. In non-lymphoid tissue, we saw a dissociation of FT protein from CD69 expression, indicating that tissue residency is not associated with tonic TCR signals. Nur77-Tempo mice, therefore, combine the temporal dynamics from the Tocky innovation with increased sensitivity of Nr4a1 to lower TCR signal strengths.

Timer

10.1093/discim/kyac009

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The role of lipids in regulating macrophage antifungal immunity

mBio (2024)

Sophie Rouvray Rebecca A. Drummond

Macrophages are critical components of the antifungal immune response. Disturbance in the number or function of these innate immune cells can significantly increase susceptibility to invasive fungal infections. Pathogenic fungi cause billions of infections every year and have an unmet clinical need, with many infections associated with unacceptably high mortality rates that primarily affect vulnerable patients with underlying immune defects. Lipid metabolism has been increasingly appreciated to significantly influence macrophage function, particularly of macrophages residing in lipid-rich organs, such as the brain, or macrophages specialized at clearing dead cells including alveolar macrophages in the lungs. In this review, we provide an overview of macrophage lipid metabolism, and discuss how lipid recycling and dysregulation affect key macrophage functions relevant for antifungal immunity including phagocytosis, functional polarization, and inflammasome activation. We focus on the fungal pathogen

10.1128/mbio.03057-23

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Interferonγ and IL-27 positively regulate type 1 regulatory T-cell development during adaptive tolerance

bioRxiv (Cold Spring Harbor Laboratory) (2024)

David A.J. Lecky Lozan Sheriff Sophie Rouvray L. George Rebecca A. Drummond

Summary Strong T-cell receptor (TCR) and IL-27 signalling influence type-1 regulatory (Tr1) T-cell development but whether other signals determine their differentiation is unclear. Utilising Tg4 TCR transgenic mice we established a model for rapid Tr1 cell induction. A single high dose of [4Y]-MBP peptide drove the differentiation of Il10 + T-cells with bona fide Tr1 cell protein and mRNA signatures. Kinetic transcriptional analysis revealed that the Tr1 cell module was transient and preceded by a burst of Ifng transcription in CD4+ T-cells. Neutralisation of IFNγ reduced Tr1 cell frequency and strong TCR signalling markers, which was correlated with reduced macrophage activation. Antibody depletion experiments inferred that T-cells – but not NK cells – provided the relevant source of IFNγ. Additionally, we show that blocking IL-27 in combination with IFNγ neutralisation additively reduced Tr1 cell frequency in vivo . These findings reveal that during strong tolerogenic TCR signalling IFN-γ has a non-redundant regulatory role in augmenting the differentiation of Tr1 cells in vivo .

10.1101/2024.06.21.598825

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Lag3 and PD-L1 govern T cell receptor signal duration in adaptively tolerised CD4⁺T cells

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Lozan Sheriff Alastair Copland David A.J. Lecky Reygn Done L. George

Abstract Anti-Lag3 and anti-PD-1 combination immunotherapy for melanoma has received recent regulatory approval, yet its mechanism of action is unclear, particularly for CD4 + T cells. Here, we determined the roles of the Lag3 and PD-1/PD-L1 pathways during CD4 + T cell activation in vivo . During primary immune responses, Lag3 played a redundant role with the PD1/PD-L1 axis dominant in regulating early CD4 + T cell activation. By exploiting an adaptive tolerance model, we reveal that Lag3 and PD-L1 co-blockade (CB) drove major changes in CD4 + T cells, resulting in a transcriptional profile dominated by a hybrid T follicular helper (Tfh)/Th17 cell phenotype. Mechanistically, CB enhanced T cell receptor (TCR) signal duration, thereby inducing an NFAT-biased transcriptional motif, previously linked to positive clinical outcomes for melanoma patients. Additionally, CB synergistically upregulated CCR6, leading to enhanced CCL20-mediated CD4 + T cell migration. Analysis of melanoma patients on anti-PD-1 pathway immunotherapies revealed that tumour CCR6 expression stratifies clinical outcomes and effector memory CD4 + T cells upregulate CCR6 in patients on anti-PD-1 and anti-Lag3 combination immunotherapy. Our data reveal that Lag3 and PD-1 pathways have context dependent roles in regulating the activation and migration of CD4 + T cells and highlights CCR6 as a biomarker for immunotherapy responses.

SIGNAL (programming language)

10.1101/2024.06.06.597762

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