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 suppresses T cells by promoting inappropriate P2Y11 receptor stimulation that impairs T cell metabolism and functions. We conclude that inhibition of LPS-induced ATP release, removal of excessive extracellular ATP, or P2Y11 receptor antagonists may be potential therapeutic strategies to prevent T cell suppression and restore host immune function in sepsis.
Highlights
T cell suppression contributes to immune dysfunction in sepsis
We have previously shown that LPS stimulation of monocytes and macrophages involves rapid ATP release that is required for IL-1 production and other antigenpresenting cells (APCs) functions [15]
In agreement with those studies, we found that LPS dose-dependently inhibited the proliferation of CD4 T cells (Fig. 1A and Fig. S1) and the production of IL-2 (Fig. 1B) in human peripheral blood mononuclear cell (PBMC) cultures
Summary
Sepsis-induced T cell suppression is characterized by impaired T cell proliferation and cytokine production [27]. Previous studies have shown that overnight incubation of peripheral blood mononuclear cell (PBMC) cultures with LPS suppresses TCR-induced T cell proliferation [10, 12]. D and E, PBMCs were treated or not with LPS (10 ng/ml) and/or anti-PD1 antibodies (1 g/ml) and stimulated with anti-CD3 antibodies for 18 h (D) or for 5 days (E), and IL-2 production or proliferation of CD4 T cells were analyzed; mean Ϯ S.D., n ϭ 2 (D) or 6 (E). Alexa488 antibodies, stimulated with anti-CD3 antibodies in the presence or absence of LPS (10 ng/ml), and briefly pelleted in Eppendorf tubes to facilitate cell-to-cell interactions, and the percentage of monocytes that formed conjugates with CD4 T cells was determined by flow cytometry after 1 h. *, p Ͻ 0.05 versus no stimulation, Kruskal–Wallis test These results demonstrate that LPS can rapidly suppress T cells, apparently without the need for de novo gene expression
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