Lymphocyte

Résumé

Les sont des cellules qui ont un rôle majeur dans le système immunitaire. En matière de structure et de fonction, on distingue trois lignées lymphocytaires différentes : les lymphocytes B et T, de petite taille, et les lymphocytes NK, de grande taille et granuleux. Les lymphocytes sont des leucocytes (globules blancs) de petite taille se trouvant principalement dans les ganglions lymphatiques et la rate. Structure Au microscope, les lymphocytes B et T apparaissent comme des cellules ovoïdes, nucléées, dont le noyau de grande taille (environ , soit le diamètre d'un globule rouge) occupe quasiment tout le corps cellulaire. Sa chromatine est disposée en mottes. Les lymphocytes B et T ne peuvent être différenciés sur de seuls critères morphologiques, mais par la nature de leurs récepteurs de surface qui déterminent leurs fonctions. Les lymphocytes NK (ou LGL : Large Granular Lymphocyt), plus grands, présentent un rapport noyau/cellule inférieur. Son noyau est échancré,

Source officielle

https://fr.wikipedia.org/wiki/Lymphocyte

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Investigation of T Lymphocyte Dynamics in an In Vitro Model of the Lymph Node Stroma

Cara Field Buchanan, Melody Swartz

Mary Ann Liebert, Inc2015

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Cancer represents one of the major public health challenges worldwide, representing more than 25% of all deaths in the European Union in 2014. It affects a large and growing part of the general population, with the National Cancer Institute (NCI) estimating that nearly 40% of men and women will be diagnosed with cancer at some point in their lifetimes.Cancer presents an enormous intrinsic complexity and diversity as well as a pronounced resistance to interventions. Current treatments are composed primarily of chemotherapy, surgery, radiotherapy and drug therapy. Each of these approaches has been met with restrained successes and limitations. One growing field of cancer treatments that is showing promising results is immunotherapy. An improved understanding of the cancer biology and microenvironment over the years, particularly the interactions between a tumor and the immune system, has demonstrated the capability of the host immune system to detect and eliminate malignant cells through the process of immune surveillance. However, by various mechanisms, malignant cells can stochastically "hide" from the immune system and transform into tumors. Immunotherapies intend to use the immune system to fight the tumor progression. Different kinds of immunotherapies exist: from immune checkpoint inhibitors (PD-1), to monoclonal antibody treatments and cancer vaccines. One interesting approach of immunotherapy is called adoptive cell transfer therapy (ACT), wherein immune cells, and more precisely, T cells, from the cancer-affected patient are extracted, allowing tumor-specific and effective T cells to be isolated, expanded, activated and re-injected into the patient's body. This type of treatment has already demonstrated great tumor clearance potential as well as the ability to induce long-term cancer immunity. However, one of the major challenges in this type of treatment is the recognition, isolation and expansion of high-affinity, effective T cells that are able to eliminate cancer cells. Several key advances in the field of genetics, sequencing, and personalized medicine have allowed for the identification of tumor-specific antigens, the unique cancer signature for a given patient and a specific tumor. But there is a growing need for novel tools and platforms enabling the screening, selection and isolation of rare, naturally-occurring, high-affinity, tumor-specific T cells. In this thesis we present a novel approach to study the affinity of CD8+ lymphocytes at the single-cell level using microfluidics technology. We demonstrate the ability of our platform to isolate single cells and evaluate their affinities towards a given antigen by using the reversible pMHC NTAmers technology developed by Julien Schmidt et al. at the Ludwig Institute for Cancer Research in Lausanne, Switzerland. The innovative platform developed here effectively alleviates some of the bottlenecks of current technologies, like flow cytometry, for affinity studies of lymphocytes at the single-cell level. This thesis represents the development from idea to proof-of-concept of this novel platform and we herein describe the origins and characterization of this technology as well as the first applications towards a personalized-medicine tool for clinical research uses.

EPFL2021

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Notch1 receptor signaling is essential for T cell fate specification and physiological thymic T lymphocyte development. Its dysregulation and oncogenic activation are detected in almost 80% of pediatric patients suffering from T cell acute lymphoblastic leukemia (T-ALL). T-ALL is a hematological neoplasm arising from immature thymocytes. T cell factor 1 (Tcf1) is a crucial well-known transcription factor regulating the early stages of thymocyte maturation and Notch1 directly drives the expression of Tcf1 during normal T cell development. Here we assessed the role of Tcf1 in modulating chromatin topology which enables the initiation of T-ALL at the level of early hematopoietic progenitors. This allows for the discovery of stage-setting epigenetic regulators establishing a leukemia-prone chromatin landscape during Notch1-driven disease initiation. We found Tcf1 to be an essential mediator of Notch1 signaling during T-ALL induction. Inactivation of Tcf1 prevented leukemogenesis despite oncogenic Notch1 activation. Genomic analysis of hematopoietic progenitors revealed T cell lineage specification to be essential in T-ALL initiation prior to the appearance of phenotypic features of T cells. The expression of genes associated with the T cell lineage was dependent on Notch1 and Tcf1. Chromatin accessibility, chromosome conformation capture and ChIP-seq analysis revealed the co-regulatory epigenetic function of Notch1 and Tcf1 in imprinting a leukemic chromatin landscape. Epigenetic modulation of distal enhancers which regulate leukemic oncogenes has been well described in patient-derived T-ALL cells. The Notch1-Myc enhancer region was shown to be indispensable in the process of leukemogenesis. We have identified a novel regulatory locus, dependent on Tcf1 and Notch1, essential for the expression of Myc in pre-T-ALL cells. This genomic region termed Tcf1-regulated Myc enhancer (TMe) was highly conserved across species. TMe was essential for the transition of pre-leukemic cells to a transplantable full-blown T-ALL but was dispensable for the physiological development of T cells. After activation of the enhancer in hematopoietic progenitors, this regulatory site remained accessible and bound by Tcf1 in murine and human T-ALL cells. Tcf1 is therefore required for shaping the epigenetic landscape of hematopoietic progenitors overexpressing oncogenic Notch1, and thus regulates the expression of genes involved in leukemogenesis.

EPFL2021

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EPFL2021