Biology subjects

Jennings, E. K.

Publications and source records attributed to Jennings, E. K..

4 recordsLinked to original sources

bioRxiv2024

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

Lag3 and PD-1 are immune checkpoints that regulate T cell responses and are current immunotherapy targets. Yet how they function to control early CD4+ T cell activation remains unclear. Here, we show that the PD-1 and Lag3 pathways exhibit layered control of the early CD4+ T cell activation process, with the effects of Lag3 more pronounced in the presence of PD-1 pathway co-blockade (CB). RNA-sequencing revealed that CB drove an early NFAT-dependent transcriptional profile, including promotion of ICOShi T follicular helper (Tfh) cell differentiation. NFAT pathway inhibition abolished CB-induced upregulation of NFAT-dependent co-receptors ICOS and OX40, whilst unaffecting the NFAT-independent gene Nr4a1. Mechanistically, Lag3 and PD-1 pathways functioned additively to regulate the duration of T cell receptor (TCR) signals during CD4+ T cell re-activation. Our data therefore reveal that PD-1 and Lag3 pathways converge to additively regulate TCR signal duration and NFAT-dependent transcriptional activity during early CD4+ T cell re-activation. HighlightsO_LIPD-1 and Lag3 pathways exhibit layered control of early CD4+ T cell activation C_LIO_LITheir co-blockade enhances NFAT-dependent TCR transcriptional programmes C_LIO_LIInhibition of NFAT signalling reverses the functional effects of PD-1 and Lag3 co-blockade C_LIO_LIMechanistically, PD-1 and Lag3 function to additively regulate TCR signal duration during re-activation of CD4+ T cells C_LI

immunology↗

bioRxiv2024

GREMLIN1 disrupts intestinal epithelial-mesenchymal crosstalk to induce a wnt-dependent ectopic stem cell niche via stromal remodelling

In homeostasis, counterbalanced morphogen signalling gradients along the vertical axis of the intestinal mucosa regulate the fate and function of epithelial and stromal cell compartments. Here, we used a disease-positioned mouse, and human tissue, to explore the consequences of pathological Bone Morphogenetic Protein (BMP) signalling dysregulation on epithelial- mesenchymal interaction. Aberrant pan-epithelial expression of the secreted BMP antagonist GREM1, resulted in ectopic crypt formation with lineage tracing demonstrating the presence of Lgr5(-) stem/progenitor cells. Isolated epithelial cell Grem1 expression had no effect on individual cell fate, indicating an intercompartmental impact of mucosal-wide BMP antagonism. Treatment with a novel anti-Grem1 antibody abrogated the polyposis phenotype, and triangulation of specific pathway inhibitors defined a pathological sequence of events, with wnt-ligand dependent ectopic stem cell niches formed through stromal remodelling following BMP disruption. These data support an emerging co-evolutionary model of intestinal cell compartmentalisation based on bidirectional regulation of epithelial-mesenchymal cell fate and function. One Sentence SummaryPathological epithelial GREM1 expression induces therapeutically reversible ectopic stem cell niches through stromal remodelling

cancer biology↗

bioRxiv2021

Antigen and Checkpoint Receptor Recalibration of T Cell Receptor Signal Strength

How T cell receptor (TCR) signal strength modulates T cell function and to what extent this is modified by immune checkpoint blockade (ICB) are key questions in immunology. Using Nr4a3-Tocky mice as a digital read-out of NFAT pathway activity, we identify the rapid quantitative and qualitative changes that occur in CD4+ T cells in response to a range of TCR signalling strengths. We demonstrate that the time and dose dependent programming of distinct co-inhibitory receptors rapidly re-calibrates T cell activation thresholds. By developing a new in vivo model, we analyse the immediate effects of ICB on T cell re-activation. Our findings reveal that anti-PD1 but not anti-Lag3 immunotherapy leads to an increased TCR signal strength. We define a strong TCR signal metric of five genes specifically upregulated by anti-PD1 in T cells (TCR.strong), which can stratify clinical outcomes during anti-PD1 monotherapy in melanoma patients. Our study therefore reveals how analysis of TCR signal strength - and its manipulation - can provide powerful metrics for monitoring outcomes to immunotherapy. Key PointsO_LITCR signal strength-dependent programming of CD4+ T cells revealed over time in vivo C_LIO_LIInhibitory receptor expression is dynamic, TCR signal strength dependent, and rapidly re-calibrates T cell activation thresholds C_LIO_LIPD1 but not Lag3 blockade leads to a unique and increased TCR signal strength signature (coined TCR.strong) C_LIO_LITCR.strong metric stratifies melanoma patient survival in response to Nivolumab (anti-PD1) therapy C_LI

immunology↗

bioRxiv2019

Distinct regulation of Nr4a receptors by NFAT and ERK signalling during T cell activation

Nr4a receptors are activated by T cell receptor (TCR) and B cell receptor (BCR) signalling and play key roles in T cell differentiation and promoting T cell exhaustion. How TCR signalling pathways regulate Nr4a receptors and their sensitivities to different physiological types of TCR signalling (e.g. tonic versus activating) remains unknown. Here we utilise Nr4a1/Nur77-GFP and Nr4a3-Tocky mice to elucidate the signalling pathways that govern Nr4a receptor expression in CD4+ and CD8+ T cells. Our findings reveal that Nr4a1-3 are Src family kinase-dependent. Moreover, Nr4a2 and Nr4a3 are abolished by calcineurin inhibitors and bind NFAT1, highlighting a necessary and sufficient role for NFAT in the control of Nr4a2 and Nr4a3, but redundancy for NFAT for Nr4a1. During T cell development, Nr4a1 is activated by tonic signalling during TCR-beta selection in the thymus, whilst Nr4a3 requires cognate peptide:MHC interactions for expression. Thus, due to differential sensitivity of Nr4a1 and Nr4a3 to TCR signalling pathways, T cells undergoing tonic versus activating TCR signalling events can be distinguished in vivo.

immunology↗