Differential regulation of P-selectin ligand expression in naive versus memory CD4+ T cells: evidence for epigenetic regulation of involved glycosyltransferase genes.
Lymphocytes are targeted to inflamed sites by specific "homing" and chemokine receptors. Most of them, including ligands for P- and E-selectin, are absent from naive CD4(+) T cells and become induced after activation and differentiation in effector/memory cells. Polarized effector cells are characterized by the rapid production of distinct cytokines upon restimulation. Their cytokine memory is in part controlled by epigenetic imprinting during differentiation. Here we ask whether a similar mechanism could regulate selectin ligand expression, mediating entry into inflamed sites, notably within the skin. We report that acquisition of selectin ligands by naive but not memory CD4(+) cells depends on progression through the G(1)/S phase of the cell cycle-a phase susceptible to modification of the chromatin structure. Cell-cycle arrest prevented transcriptional activation of glycosyltransferases involved in the generation of selectin ligands, suggesting that progression through the cell cycle is required to unlock their genes. Artificial DNA demethylation strongly increased the frequency of selectin ligand-expressing cells, suggesting that DNA methylation keeps transferase genes inaccessible in naive T cells. Due to these findings we propose that selectin-dependent inflammation-seeking properties are imprinted by epigenetic modifications upon T-cell differentiation into effector cells.
Experimentelle Rheumatologie, Medizinische Klinik, Charité Universitätsmedizin Berlin, Germany.
Uta
U
Syrbe
Silke
S
Jennrich
Arndt
A
Schottelius
Anne
A
Richter
Andreas
A
Radbruch
Alf
A
Hamann
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D044127:Epigenesis, Genetic / Q000276:immunology; D005647:Fucosyltransferases / Q000235:genetics; D016193:G1 Phase; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D016695:Glycosyltransferases / Q000235:genetics*; D007156:Immunologic Memory / Q000502:physiology; D008024:Ligands; D008745:Methylation; D051379:Mice; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D019007:P-Selectin / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016196:S Phase
D008024:Ligands; D019007:P-Selectin; D012333:RNA, Messenger; D016695:Glycosyltransferases; D005647:Fucosyltransferases; D017351:N-Acetylglucosaminyltransferases; C053024:beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase; C031692:galactoside 3-fucosyltransferase