title: 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.affiliation: Departments of Surgery.
authors.forename: Carola
authors.initials: C
authors.lastname: Ledderose
authors.affiliation: Departments of Surgery.
authors.forename: Yi
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Departments of Surgery.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ledderose
authors.affiliation: Departments of Surgery Department of Anesthesiology, Ludwig-Maximilian University of Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Woehrle
authors.affiliation: Departments of Surgery.
authors.forename: Maria
authors.initials: M
authors.lastname: Heinisch
authors.affiliation: Department of Surgery, University of California, San Diego Department of Medicine, Division of Immunology and Rheumatology, Stanford University, California.
authors.forename: Linda
authors.initials: L
authors.lastname: Yip
authors.affiliation: Departments of Surgery.
authors.forename: Jingping
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Medicine.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.affiliation: Emergency Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nathan I
authors.initials: NI
authors.lastname: Shapiro
authors.affiliation: Departments of Surgery Department of Surgery, University of California, San Diego Ludwig Boltzmann Institute for Traumatology, Vienna, Austria.
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Junger
mesh_terms: D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000502:physiology*; D011687:Purines / Q000378:metabolism*; D011983:Receptors, Purinergic / Q000502:physiology*; D018805:Sepsis / Q000276:immunology*; D013498:Suramin; D055815:Young Adult
chemical_list: D011687:Purines; D011983:Receptors, Purinergic; D013498:Suramin
keywords: T cell suppression; mitochondrial dysfunction; purinergic signaling; sepsis