title: Gut memories do not fade: epigenetic regulation of lasting gut homing receptor expression in CD4+memory T cells.
abstract: The concept of a "topographical memory" in lymphocytes implies a stable expression of homing receptors mediating trafficking of lymphocytes back to the tissue of initial activation. However, a significant plasticity of the gut-homing receptor α4β7was found in CD8+T cells, questioning the concept. We now demonstrate that α4β7expression in murine CD4+memory T cells is, in contrast, imprinted and remains stable in the absence of the inducing factor retinoic acid (RA) or other stimuli from mucosal environments. Repetitive rounds of RA treatment enhanced the stability of de novo induced α4β7. A novel enhancer element in the murine Itga4 locus was identified that showed, correlating to stability, selective DNA demethylation in mucosa-seeking memory cells and methylation-dependent transcriptional activity in a reporter gene assay. This implies that epigenetic mechanisms contribute to the stabilization of α4β7expression. Analogous DNA methylation patterns could be observed in the human ITGA4 locus, suggesting that its epigenetic regulation is conserved between mice and men. These data prove that mucosa-specific homing mediated by α4β7is imprinted in CD4+memory T cells, reinstating the validity of the concept of "topographical memory" for mucosal tissues, and imply a critical role of epigenetic mechanisms.
authors.affiliation: Experimental Rheumatology, Charité Universitätsmedizin Berlin, and Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany.
authors.forename: B A
authors.initials: BA
authors.lastname: Szilagyi
authors.affiliation: Experimental Rheumatology, Charité Universitätsmedizin Berlin, and Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Triebus
authors.affiliation: Experimental Rheumatology, Charité Universitätsmedizin Berlin, and Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kressler
authors.affiliation: Experimental Rheumatology, Charité Universitätsmedizin Berlin, and Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: de Almeida
authors.affiliation: Saarland University, FR8.3 Genetics/Epigenetics, Saarbrücken, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Tierling
authors.affiliation: Experimental Rheumatology, Charité Universitätsmedizin Berlin, and Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Durek
authors.affiliation: Experimental Rheumatology, Charité Universitätsmedizin Berlin, and Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Mardahl
authors.affiliation: Experimental Rheumatology, Charité Universitätsmedizin Berlin, and Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Szilagyi
authors.affiliation: Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Floess
authors.affiliation: Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Huehn
authors.affiliation: Charité Universitätsmedizin Berlin, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Berlin, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Syrbe
authors.affiliation: Saarland University, FR8.3 Genetics/Epigenetics, Saarbrücken, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Walter
authors.affiliation: Experimental Rheumatology, Charité Universitätsmedizin Berlin, and Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany.
authors.forename: J K
authors.initials: JK
authors.lastname: Polansky
authors.affiliation: Experimental Rheumatology, Charité Universitätsmedizin Berlin, and Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hamann
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement; D002478:Cells, Cultured; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic / Q000235:genetics; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D007156:Immunologic Memory; D039441:Integrin alpha4 / Q000235:genetics / Q000378:metabolism*; D039641:Integrin beta Chains / Q000378:metabolism; D007422:Intestines / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014212:Tretinoin / Q000378:metabolism
chemical_list: D039641:Integrin beta Chains; D016201:Receptors, Lymphocyte Homing; C091368:integrin beta7; D039441:Integrin alpha4; D014212:Tretinoin