title: Differential localization and function of ADP-ribosylation factor-6 in anergic human T cells: a potential marker for their identification.
abstract: Anergy is a state of immunologic tolerance in which T cells are viable but incapable of responding to antigenic stimulation. Recent data indicate that anergic cells have a distinct gene expression program that determines their unique function. In this study we show that anergic human T cells selectively express the small GTPase ADP-ribosylation factor-6 (ARF6), which is involved in membrane traffic and regulation of the cortical actin cytoskeleton. ARF6 was expressed in the GTP-bound form that localizes at the plasma membrane, resulting in a distinct morphologic appearance of anergic cells. Forced expression of ARF6-GTP in Jurkat T cells prevented TCR-mediated reorganization of cortical actin, extracellular signal-regulated kinase1/2 activation, and IL-2 transcription. Forced expression of ARF6-GTP in primary human T cells inhibited extracellular signal-regulated kinase1/2 activation and proliferative responses. Importantly, T cells with the distribution pattern of ARF6-GTP were detected in peripheral blood, suggesting that anergic T cells may constitutively exist in vivo.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute, Division of Medical Oncology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tzachanis
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Appleman
authors.forename: Andre A F L
authors.initials: AA
authors.lastname: Van Puijenbroek
authors.forename: Alla
authors.initials: A
authors.lastname: Berezovskaya
authors.forename: Lee M
authors.initials: LM
authors.lastname: Nadler
authors.forename: Vassiliki A
authors.initials: VA
authors.lastname: Boussiotis
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism* / Q000502:physiology*; D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology*; D002999:Clone Cells; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005822:Genetic Vectors; D006160:Guanosine Triphosphate / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000097:blood; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic / Q000276:immunology; D014162:Transfection
chemical_list: D000089982:ADP-Ribosylation Factor 6; D000199:Actins; D015415:Biomarkers; D007376:Interleukin-2; D008565:Membrane Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D006160:Guanosine Triphosphate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human