Research ArticleImmunology

T cell–derived soluble glycoprotein GPIbα mediates PGE2 production in human monocytes activated with the vaccine adjuvant MDP

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Science Signaling  08 Oct 2019:
Vol. 12, Issue 602, eaat6023
DOI: 10.1126/scisignal.aat6023

Vaccine reactions are a multicellular affair

Vaccine adjuvants can cause adverse, sometimes life-threatening, immune reactions in patients. The adjuvant MDP activates monocytes to release an inflammatory prostaglandin and cytokines. However, Liu et al. found that MDP administration to human monocytes alone was insufficient to produce the prostaglandin response that they saw when it was administered to rabbits. Instead, the authors found that MDP induced T cells to release the glycoprotein GPIbα (better known in platelets), which stimulated Ca2+ signaling by a receptor on the monocytes, resulting in prostaglandin production. Knocking out the GPIbα receptor prevented the inflammatory response to MDP in mice. This multicellular mechanism may underlie adverse vaccine reactions in humans.


Vaccine adjuvants containing analogs of microbial products activate pattern recognition receptors (PRRs) on antigen-presenting cells, including monocytes and macrophages, which can cause prostaglandin E2 (PGE2) release and consequently undesired inflammatory responses and fever in vaccine recipients. Here, we studied the mechanism of PGE2 production by human monocytes activated with muramyl dipeptide (MDP) adjuvant, which activates cytosolic nucleotide-binding oligomerization domain 2 (NOD2). In rabbits, administration of MDP elicited an early increase in PGE2 followed by fever. In human monocytes, MDP alone did not induce PGE2 production. However, high amounts of PGE2 and the proinflammatory cytokines IL-1β and IL-6 were secreted by monocytes activated with MDP in the presence of conditioned medium obtained from CD3 bead–isolated T cells (Tc CM) but not from those isolated without CD3 beads. Mass spectrometry and immunoblotting revealed that the costimulatory factor in Tc CM was glycoprotein Ib α (GPIbα). Antibody-mediated blockade of GPIbα or of its receptor, Mac-1 integrin, inhibited the secretion of PGE2, IL-1β, and IL-6 in MDP + Tc CM–activated monocytes, whereas recombinant GPIbα protein increased PGE2 production by MDP-treated monocytes. In vivo, COX2 mRNA abundance was reduced in the liver and spleen of Mac-1 KO mice after administration of MDP compared with that of treated wild-type mice. Our findings suggest that the production of PGE2 and proinflammatory cytokines by MDP-activated monocytes is mediated by cooperation between two signaling pathways: one delivered by MDP through NOD2 and a second through activation of Mac-1 by T cell–derived GPIbα.

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