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.
Highlights
Control of immunologic tolerance and homeostasis rely on Foxp31CD41CD251 regulatory T cells (Tregs) that constitutively express the high affinity receptor for Interleukin-2, CD25
Different IL2/anti-Interleukin 2 (IL-2) antibody complexes induce distinct responses in vivo, depending on the epitope of IL-2 bound by the particular antibody: mouse IL-2 in complex with mAb JES6-1A12 or human IL-2 in complex with mAb 5344 induce the preferential expansion of Tregs, whereas mouse IL-2 in complex with mAb S4B6 or human IL-2 in complex with mAb-602 induce the preferential expansion of CD81 cytotoxic T cells and NK cells[23,24,25,26,27,28]
We propose that ADP-ribosylation of CD25 provides an endogenous mechanism to tune IL-2 signaling in response to NAD1 released from injured cells during inflammation and tissue damage
Summary
Control of immunologic tolerance and homeostasis rely on Foxp31CD41CD251 regulatory T cells (Tregs) that constitutively express the high affinity receptor for Interleukin-2, CD25. Different IL2/anti-IL-2 antibody complexes induce distinct responses in vivo, depending on the epitope of IL-2 bound by the particular antibody: mouse IL-2 in complex with mAb (monoclonal antibody) JES6-1A12 or human IL-2 in complex with mAb 5344 induce the preferential expansion of Tregs, whereas mouse IL-2 in complex with mAb S4B6 or human IL-2 in complex with mAb-602 induce the preferential expansion of CD81 cytotoxic T cells and NK cells[23,24,25,26,27,28] These findings raise the question whether endogenous mechanisms exist that could modulate IL-2 signaling in vivo. The NAD1-dependent toxin-related ADPribosyltransferase ARTC2.2 is a GPI-anchored enzyme expressed on the cell membrane of naıve T cells and Foxp31CD41CD251 regulatory T cells (Tregs)[35,36,37]. ADP-ribosylation of cell surface proteins can be monitored by autoradiography or by antibody-based immunoassays (Supplementary Fig. 1c, d)
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