Lipopolysaccharide suppresses T cells by generating extracellular ATP that impairs their mitochondrial function via P2Y11 receptors

The Journal of Biological Chemistry
Koichiro SueyoshiWolfgang G Junger

Abstract

T cell suppression contributes to immune dysfunction in sepsis. However, the underlying mechanisms are not well-defined. Here, we show that exposure of human peripheral blood mononuclear cells to bacterial lipopolysaccharide (LPS) can rapidly and dose-dependently suppress interleukin-2 (IL-2) production and T cell proliferation. We also report that these effects depend on monocytes. LPS did not prevent the interaction of monocytes with T cells, nor did it induce programmed cell death protein 1 (PD-1) signaling that causes T cell suppression. Instead, we found that LPS stimulation of monocytes led to the accumulation of extracellular ATP that impaired mitochondrial function, cell migration, IL-2 production, and T cell proliferation. Mechanistically, LPS-induced ATP accumulation exerted these suppressive effects on T cells by activating the purinergic receptor P2Y11 on the cell surface of T cells. T cell functions could be partially restored by enzymatic removal of extracellular ATP or pharmacological blocking of P2Y11 receptors. Plasma samples obtained from sepsis patients had similar suppressive effects on T cells from healthy subjects. Our findings suggest that LPS and ATP accumulation in the circulation of sepsis patients sup...Continue Reading

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Citations

Oct 22, 2019·Journal of Leukocyte Biology·Mausita Karmakar, George R Dubyak
Feb 11, 2020·International Reviews of Immunology·Marharyta Zyma, Rafał Pawliczak
Feb 27, 2020·Journal for Immunotherapy of Cancer·David AllardJohn Stagg
Jul 8, 2020·International Journal of Molecular Sciences·Gonzalo de la RosaPablo Pelegrín
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Feb 2, 2021·Frontiers in Pharmacology·Raíssa Leite-AguiarRobson Coutinho-Silva
Nov 3, 2020·Frontiers in Immunology·Carola Ledderose, Wolfgang G Junger

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