Packed red blood cells inhibit T-cell activation via ROS-dependent signaling pathways

Abstract

Numerous observations indicate that red blood cells (RBCs) affect T-cell activation and proliferation. We have studied effects of packed RBCs (PRBCs) on T-cell receptor (TCR) signaling and the molecular mechanisms whereby (P)RBCs modulate T-cell activation. In line with previous reports, PRBCs attenuated the expression of T-cell activation markers CD25 and CD69 upon costimulation via CD3/CD28. In addition, T-cell proliferation and cytokine expression were markedly reduced when T-cells were stimulated in the presence of PRBCs. Inhibitory activity of PRBCs required direct cell–cell contact and intact PRBCs. The production of activation-induced cellular reactive oxygen species, which act as second messengers in T-cells, was completely abrogated to levels of unstimulated T-cells in the presence of PRBCs. Phosphorylation of the TCR-related zeta chain and thus proximal TCR signal transduction was unaffected by PRBCs, ruling out mechanisms based on secreted factors and steric interaction restrictions. In large part, downstream signaling events requiring reactive oxygen species for full functionality were affected, as confirmed by an untargeted MS-based phosphoproteomics approach. PRBCs inhibited T-cell activation more efficiently than treatment with 1 mM of the antioxidant N -acetyl cysteine. Taken together, our data imply that inflammation-related radical reactions are modulated by PRBCs. These immunomodulating effects may be responsible for clinical observations associated with transfusion of PRBCs.

Metabo-tip: a metabolomics platform for lifestyle monitoring supporting the development of novel strategies in predictive, preventive and personalised medicine

“…We have recently reported that erythrocytes interfere with reactive oxygen species (ROS) formation so efficiently that ROS-dependent T-cell activation is blocked by the mere presence of erythrocytes [ 58 ]. This observation clearly implies that the formation of ROS-dependent metabolites in blood may be inhibited as well.…”

Erythrocytes as Messengers for Information and Energy Exchange between Cells

“…Erythrocytes also interact with other cells of the immune system. Erythrocytes have been shown to inhibit T cell activation or activation-induced apoptosis presumably via reactive oxygen species-dependent pathways [123,124]. Erythrocytes treated with a cancer cell line stimulated T cells to more proliferation and other cytokine secretion profile than if treated with control erythrocytes [125].…”

Unexplored Roles of Erythrocytes in Atherothrombotic Stroke

“…Erythrocyte antioxidant capacity can halter T-cell activation. However, under the oxidant environment of atherothrombosis, erythrocytes are unable to neutralize the ROS related to T-cell activation [ 47 , 48 ]. This incapability of controlling T-cell activation can be provoked by high glucose, homocysteine, and other metabolites.…”