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J Infect Dis. 2016 Feb 1;213(3):456-64. doi: 10.1093/infdis/jiv373. Epub 2015 Jul 6.

Mitochondrial Dysfunction, Depleted Purinergic Signaling, and Defective T Cell Vigilance and Immune Defense.

Author information

1
Departments of Surgery.
2
Departments of Surgery Department of Anesthesiology, Ludwig-Maximilian University of Munich, Germany.
3
Department of Surgery, University of California, San Diego Department of Medicine, Division of Immunology and Rheumatology, Stanford University, California.
4
Medicine.
5
Emergency Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
6
Departments of Surgery Department of Surgery, University of California, San Diego Ludwig Boltzmann Institute for Traumatology, Vienna, Austria.

Abstract

T cell suppression in sepsis is a well-known phenomenon; however, the underlying mechanisms are not fully understood. Previous studies have shown that T cell stimulation up-regulates mitochondrial adenosine triphosphate (ATP) production to fuel purinergic signaling mechanisms necessary for adequate T cell responses. Here we show that basal mitochondrial ATP production, ATP release, and stimulation of P2X1 receptors represent a standby purinergic signaling mechanism that is necessary for antigen recognition. Inhibition of this process impairs T cell vigilance and the ability of T cells to trigger T cell activation, up-regulate mitochondrial ATP production, and stimulate P2X4 and P2X7 receptors that elicit interleukin 2 production and T cell proliferation. T cells of patients with sepsis lack this standby purinergic signaling system owing to defects in mitochondrial function, ATP release, and calcium signaling. These defects impair antigen recognition and T cell function and are correlated with sepsis severity. Pharmacological targeting of these defects may improve T cell function and reduce the risk of sepsis.

KEYWORDS:

T cell suppression; mitochondrial dysfunction; purinergic signaling; sepsis

PMID:
26150546
PMCID:
PMC4704665
DOI:
10.1093/infdis/jiv373
[Indexed for MEDLINE]
Free PMC Article

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