title: Tuning IL-2 signaling by ADP-ribosylation of CD25.
abstract: Control of immunologic tolerance and homeostasis rely on Foxp3(+)CD4(+)CD25(+) regulatory T cells (Tregs) that constitutively express the high affinity receptor for Interleukin-2, CD25. Tregs proliferate in response to injections of IL-2/anti-IL-2 antibody complexes or low doses of IL-2. However, little is known about endogenous mechanisms that regulate the sensitivity of CD25 to signaling by IL-2. Here we demonstrate that CD25 is ADP-ribosylated at Arg35 in the IL-2 binding site by ecto-ADP-ribosyltransferase ARTC2.2, a toxin-related GPI-anchored ecto-enzyme. ADP-ribosylation inhibits binding of IL-2 by CD25, IL-2- induced phosphorylation of STAT5, and IL-2-dependent cell proliferation. Our study elucidates an as-yet-unrecognized mechanism to tune IL-2 signaling. This newly found mechanism might thwart Tregs at sites of inflammation and thereby permit a more potent response of activated effector T cells.
authors.affiliation: Institute of Immunology, University Medical Center, 20246 Hamburg, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Teege
authors.affiliation: Institute of Immunology, University Medical Center, 20246 Hamburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hann
authors.affiliation: Institute of Immunology, University Medical Center, 20246 Hamburg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Miksiewicz
authors.affiliation: Institute of Immunology, University Medical Center, 20246 Hamburg, Germany.
authors.forename: Cary
authors.initials: C
authors.lastname: MacMillan
authors.affiliation: Institute of Immunology, University Medical Center, 20246 Hamburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Rissiek
authors.affiliation: Department of Clinical Chemistry, University Medical Center, 20246 Hamburg, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Buck
authors.affiliation: Institute of Immunology, University Medical Center, 20246 Hamburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Menzel
authors.affiliation: Institute of Immunology, University Medical Center, 20246 Hamburg, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Nissen
authors.affiliation: 1] Institute of Immunology, University Medical Center, 20246 Hamburg, Germany [2] Department of Radiology, University Medical Center, 20246 Hamburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bannas
authors.affiliation: Institute of Immunology, University Medical Center, 20246 Hamburg, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Haag
authors.affiliation: 1] Normandy University, Institute for Research and Innovation in Biomedicine, 76183 Rouen, France [2] Inserm, U905, 76000 Rouen, France [3] Rouen University Hospital, Department of Immunology, 76000 Rouen, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Boyer
authors.affiliation: 1] Normandy University, Institute for Research and Innovation in Biomedicine, 76183 Rouen, France [2] Inserm, U905, 76000 Rouen, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Seman
authors.affiliation: 1] Normandy University, Institute for Research and Innovation in Biomedicine, 76183 Rouen, France [2] Inserm, U905, 76000 Rouen, France.
authors.forename: Sahil
authors.initials: S
authors.lastname: Adriouch
authors.affiliation: 1] Institute of Immunology, University Medical Center, 20246 Hamburg, Germany [2] Normandy University, Institute for Research and Innovation in Biomedicine, 76183 Rouen, France.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Koch-Nolte
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D050799:STAT5 Transcription Factor; D000246:Adenosine Diphosphate Ribose; C043357:ADP-ribosylarginine