Tuning IL-2 signaling by ADP-ribosylation of CD25

Sci Rep. 2015 Mar 10;5:8959. doi: 10.1038/srep08959.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate Ribose / analogs & derivatives
  • Adenosine Diphosphate Ribose / metabolism
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Proliferation / genetics
  • HEK293 Cells
  • Humans
  • Immune Tolerance*
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism*
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Interleukin-2 Receptor alpha Subunit / metabolism*
  • Mice
  • Phosphorylation
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*

Substances

  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • STAT5 Transcription Factor
  • Adenosine Diphosphate Ribose
  • ADP-ribosylarginine