title: Inducible chromatin priming is associated with the establishment of immunological memory in T cells.
abstract: Immunological memory is a defining feature of vertebrate physiology, allowing rapid responses to repeat infections. However, the molecular mechanisms required for its establishment and maintenance remain poorly understood. Here, we demonstrated that the first steps in the acquisition of T-cell memory occurred during the initial activation phase of naïve T cells by an antigenic stimulus. This event initiated extensive chromatin remodeling that reprogrammed immune response genes toward a stably maintained primed state, prior to terminal differentiation. Activation induced the transcription factors NFAT and AP-1 which created thousands of new DNase I-hypersensitive sites (DHSs), enabling ETS-1 and RUNX1 recruitment to previously inaccessible sites. Significantly, these DHSs remained stable long after activation ceased, were preserved following replication, and were maintained in memory-phenotype cells. We show that primed DHSs maintain regions of active chromatin in the vicinity of inducible genes and enhancers that regulate immune responses. We suggest that this priming mechanism may contribute to immunological memory in T cells by facilitating the induction of nearby inducible regulatory elements in previously activated T cells.
authors.affiliation: Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham, UK.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Bevington
authors.affiliation: Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cauchy
authors.affiliation: Warwick Systems Biology Centre, University of Warwick, Coventry, UK.
authors.forename: Jason
authors.initials: J
authors.lastname: Piper
authors.affiliation: Section of Experimental Haematology, Leeds Institute for Molecular Medicine, University of Leeds, Leeds, UK.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bertrand
authors.affiliation: Warwick Systems Biology Centre, University of Warwick, Coventry, UK.
authors.forename: Naveen
authors.initials: N
authors.lastname: Lalli
authors.affiliation: Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham, UK.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Jarvis
authors.affiliation: Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham, UK.
authors.forename: Liam Niall
authors.initials: LN
authors.lastname: Gilding
authors.affiliation: Warwick Systems Biology Centre, University of Warwick, Coventry, UK.
authors.forename: Sascha
authors.initials: S
authors.lastname: Ott
authors.affiliation: Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham, UK.
authors.forename: Constanze
authors.initials: C
authors.lastname: Bonifer
authors.affiliation: Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham, UK p.n.cockerill@bham.ac.uk.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Cockerill
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054402:Chemokine CCL1 / Q000235:genetics; D002843:Chromatin / Q000378:metabolism*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D003850:Deoxyribonuclease I / Q000378:metabolism; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006801:Humans; D007156:Immunologic Memory; D007377:Interleukin-3 / Q000235:genetics; D019169:Jurkat Cells; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000235:genetics; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics
chemical_list: C502258:Ccl1 protein, mouse; D054402:Chemokine CCL1; D002843:Chromatin; D050676:Core Binding Factor Alpha 2 Subunit; C494042:Ets1 protein, mouse; C508596:IL3 protein, human; D007377:Interleukin-3; D050778:NFATC Transcription Factors; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; C493726:Runx1 protein, mouse; D018808:Transcription Factor AP-1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003850:Deoxyribonuclease I
keywords: chromatin; epigenetics; gene regulation; immunity; memory T cell