Teege Sophie, Hann Alexander, Miksiewicz Maria, MacMillan Cary, Rissiek Björn, Buck Friedrich, Menzel Stephan, Nissen Marion, Bannas Peter, Haag Friedrich, Boyer Olivier, Seman Michel, Adriouch Sahil, Koch-Nolte Friedrich
Institute of Immunology, University Medical Center, 20246 Hamburg, Germany.
Department of Clinical Chemistry, University Medical Center, 20246 Hamburg, Germany.
Sci Rep. 2015 Mar 10;5:8959. doi: 10.1038/srep08959.
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.
免疫耐受和内环境稳态的维持依赖于组成性表达白细胞介素-2（IL-2）高亲和力受体CD25的Foxp3(+)CD4(+)CD25(+)调节性T细胞（Tregs）。Tregs会对注射的IL-2/抗IL-2抗体复合物或低剂量IL-2产生增殖反应。然而，关于调节CD25对IL-2信号敏感性的内源性机制，人们了解甚少。在此，我们证明CD25在IL-2结合位点的精氨酸35处被胞外ADP-核糖基转移酶ARTC2.2进行ADP-核糖基化修饰，ARTC2.2是一种与毒素相关的糖基磷脂酰肌醇锚定的胞外酶。ADP-核糖基化抑制了CD25对IL-2的结合、IL-2诱导的信号转导和转录激活因子5（STAT5）的磷酸化以及IL-2依赖的细胞增殖。我们的研究阐明了一种尚未被认识的调节IL-2信号的机制。这一新发现的机制可能在炎症部位抑制Tregs，从而使活化的效应T细胞产生更强有力的反应。
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