Coordination between TLR9 Signaling in Macrophages and CD3 Signaling in T Cells Induces Robust Expression of IL-30

Abstract

Interleukin 30 (IL30), the p28 subunit of IL27, interacts with Epstein-Barr virus induced gene 3 to form IL27, which modulates both pro- and anti-inflammatory responses during autoimmune or infectious disease. It also acts as a natural antagonist of glycoprotein 130 (gp130), thereby attenuating the signals of other gp130-associated cytokines. IL30 regulation via LPS has been reported by others, but the intercellular communication that induces IL30 expression is unknown. Here, we show that treatment with anti-CD3/CD28 antibodies plus CpG oligodeoxynucleotides induces robust expression of IL30, whereas either treatment alone induces only low expression of IL30. This observation in vitro mirrors murine model in which administration of CpG under inflammatory conditions in vivo induces IL30 expression. This robust induction of IL30 occurs through the coordination of helper CD4+ T cells and innate immune cells (such as macrophages) and, to a lesser degree, B cells via the CD40/CD154 signaling pathway. These findings reveal a previously unrecognized mechanism that integrates signaling pathways from T cells and macrophages at the cellular level to induce IL30 expression.

Ginsenoside compound K suppresses the abnormal activation of T lymphocytes in mice with collagen-induced arthritis

“…Mononuclear spleen cell suspensions were incubated with beads in PBS and were then washed and purified using an automated magnetic cell sorter. More than 98% of CD3 + T cells and pan B cells were harvested, as determined by fluorescence-activated cell sorting (FACS) [31] .…”

The TLR7 ligand R848 prevents mouse graft-versus-host disease and cooperates with anti-interleukin-27 antibody for maximal protection and regulatory T-cell upregulation

“…10,11 This last, a member of the IL-6 and IL-12 families, is a cytokine with multiple activities 12 that both promotes Th1 type immune reactions 13 and restrains excessive inflammation. 14 IL-27 is formed by non-covalently linked p28 (also called IL-30) 15 and Epstein-Barr virus-induced gene 3 product (EBI3), which are structurally related to IL-12p35 and IL-12p40, respectively. 13 IL-27 binds to a heterodimeric receptor, comprising WSX-1/IL-27Rα and gp130.…”

Dual Roles of IFN-γ and IL-4 in the Natural History of Murine Autoimmune Cholangitis: IL-30 and Implications for Precision Medicine

“…IL-30, a subunit p28 of IL-27, has been detected in macrophages, dendritic cells, and hepatocytes 13 41 . Induction of high expression of IL-30 occurs with the coordination of activated T cells 42 . In liver injury, IL-30 suppresses the intrinsic ability of CD4 + T cells to produce IFN-γ in acute liver inflammation 13 41 and IL-30 attenuates liver fibrosis by recruiting natural-killer–like T cells to the liver to remove activated hepatic stellate cells 43 .…”