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

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.

• Authors: Carola Ledderose, Yi Bao, Stephan Ledderose, Tobias Woehrle, Maria Heinisch, Linda Yip, Jingping Zhang, Simon C Robson, Nathan I Shapiro, Wolfgang G Junger
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 213 Issue 3 Pg. 456-64 (Feb 01 2016) ISSN: 1537-6613 [Electronic] United States
• PMID: 26150546 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected].

Chemical References

• Purines
• Receptors, Purinergic
• Suramin

Topics

• Adolescent
• Adult
• CD4-Positive T-Lymphocytes (physiology)
• Calcium Signaling (physiology)
• Humans
• Jurkat Cells
• Mitochondria (physiology)
• Purines (metabolism)
• Receptors, Purinergic (physiology)
• Sepsis (immunology)
• Suramin
• Young Adult