Remin-T · Dissecting the molecular basis of immunological memory in human T cells
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2023-09-01 → 2025-08-31
- EU contribution
- €187,624
- Participants
- 1
- Scheme
- HORIZON-TMA-MSCA-PF-EF
Lines connect the coordinator with its partners.
Results in brief
Dissecting the molecular basis of immunological memory in human T cells
T cells are essential for immunity to pathogens and malignancies. While the initial activation of a naive T cell – that has never encountered its target antigen (such as a pathogen- or tumour-derived protein) – is slow (multiple days), experienced or 'memory' T cells launch powerful ‘recall’ responses that are both faster (hours) and greater in magnitude. These memory T cells provide long-lasting immunological protection against previously encountered harmful agents – forming the basis of the current vaccination strategies. However, the formation of memory T cells is not without risk. Aberrant memory T cells targeting harmless (self)antigens can cause autoimmunity (worldwide prevalence of ~4%) or allergy (most prevalent type of chronic disease in Europe affecting 10-40% of EU citizens). In addition, in patients with cancer – who account for an estimated global death toll of 10 million per year – T cells often fail to adopt functional memory phenotypes and instead enter a state of relative dysfunction. This leads to failed anti-tumor immunity and partly explains the modest clinical success of current cancer immunotherapies. Unraveling the molecular basis of memory in T cells is key to developing improved vaccination strategies and T cell–based immunotherapies. Evidence is emerging that the rapid recall ability of memory T cells may rely on dynamic changes at the chromatin or epigenome level. However, we lack a mechanistic understanding of how memory T cells durably ‘remember’ gene regulatory processes essential for high-magnitude protective immune responses. Most importantly, the molecular determinants that coordinate the maintenance of transcriptional memory in T cells remain unknown. This HE-MSCA-PF project employs an innovative epigenomics approach to uncover the molecular circuitry underlying immunological memory in primary human T cells. Specifically, this project addresses the following key objectives: • Objective 1: Multidimensional epigenomics of naive and memory T cells during activation • Objective 2: Computational data integration to identify mechanisms and drivers of memory recall • Objective 3: Functional validation of candidate genes, gene regulatory elements and/or biological processes underlying T cell memory recall
Data: CORDIS, © European Union
Project objective
T lymphocytes are essential for immunity to pathogens and malignancies. Activated T cells can retain a memory imprint of their adversary (e.g. a virus), enabling them to respond more rapidly and vigorously to any subsequent encounters. While memory T cell formation is critical for successful vaccination and anti-tumor immunity, dysfunctional memory T cells are a common feature of human disease, including allergy, autoimmunity and cancer. T cell activation emerges from changes in gene expression dictated by intricate chromatin dynamics. Recently, 3D chromatin folding emerged as a key regulator of transcriptional control by ensuring correct communication between regulatory elements and their target genes. How memory T cells leverage three-dimensionally organized chromatin configurations to achieve rapid re-activation of specific inflammatory genes is unclear. Hence, the molecular mechanisms that control and maintain immunological memory remain poorly understood. To address this issue, I propose an innovative molecular strategy to dissect immunological memory in primary human CD4+ T cells that combines cutting-edge genome-wide analyses of gene expression, chromatin state and three-dimensional (3D) genome folding with CRISPR/Cas9-based functional assays. This approach will generate the first integrated multidimensional epigenome atlas of a human T cell memory recall response, yielding molecular circuits of genes, regulatory elements and biological pathways underlying human immunological memory. Multimodal single cell genomics assays will reveal the nature of transcriptome-epigenome crosstalk in individual T cells and the heterogeneity of memory recall. These insights will force a breakthrough in our understanding of how human immune cells maintain specific transcriptional programs for launching rapid and tailored responses upon re-activation, and how this feeds into susceptibility to develop disease.
Original text from CORDIS.
Participants
- ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM · RotterdamCoordinatorNetherlands
Links
Data: CORDIS, © European Union