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Transcriptional control of innate memory CD8+ T cells

CD8+ T cells are essential for host protection against intracellular pathogens and tumors. During antigen-driven responses, CD8+ T cell fate is governed by transcriptional and epigenetic processes that allow naïve CD8+ T cells to develop into a wide range of effector and conventional memory cell subsets. Over the last decades, novel techniques and major efforts led to a better understanding of the origin, nature, and short- and long-term effects of these processes on individual CD8+ T cells. Under certain conditions, naïve CD8+ T cells can acquire memory phenotype and functions in an antigen-independent manner. Although homeostatic cytokines and initial activation pathways that drive the development of these unconventional memory cells had been identified, the ensuing transcriptional profile of these cells and their degree of similarity with conventional memory cells remained ill-defined. The epigenetic events that accompany unconventional memory formation were also not known.Here, we show that innate memory cells, a type of thymic unconventional memory cells, are transcriptionally close to conventional memory cells but only partially epigenetically programmed toward the full memory fate. We also show that the sole overexpression of the transcription factor Eomesodermin (EOMES), a master regulator of effector and conventional memory cells, is able to drive many of the phenotypical, functional, transcriptional, and epigenetic features of innate memory cells, and to induce the recruitment of BRG1, a member of chromatin remodeling complexes, to innate memory gene regulatory regions. We further show that the in vivo interleukine-4-dependent development of innate memory cells is largely dependent on BRG1. We bring to light that, in innate memory cells, EOMES is recruited in many instances to genomic regions previously bound by the transcription factor RUNX3. Overall, we provide insights into the mechanisms that allow memory cell formation and T cell receptor stimulation to be uncoupled. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

Identiferoai:union.ndltd.org:ulb.ac.be/oai:dipot.ulb.ac.be:2013/295204
Date25 November 2019
CreatorsIstaces, Nicolas
ContributorsGoriely, Stanislas, Corazza, Francis, Muraille, Eric, Stamatopoulos, Basile, Wittamer, Valérie, Dewals, Benjamin, Taghon, Tom
PublisherUniversite Libre de Bruxelles, Université libre de Bruxelles, Faculté de Médecine – Médecine, Bruxelles
Source SetsUniversité libre de Bruxelles
LanguageEnglish
Detected LanguageEnglish
Typeinfo:eu-repo/semantics/doctoralThesis, info:ulb-repo/semantics/doctoralThesis, info:ulb-repo/semantics/openurl/vlink-dissertation
Format3 full-text file(s): application/vnd.openxmlformats-officedocument.wordprocessingml.document | application/pdf | application/pdf
Rights3 full-text file(s): info:eu-repo/semantics/openAccess | info:eu-repo/semantics/restrictedAccess | info:eu-repo/semantics/closedAccess

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