title: Mitochondria are gate-keepers of T cell function by producing the ATP that drives purinergic signaling.
abstract: T cells play a central role in host defense. ATP release and autocrine feedback via purinergic receptors has been shown to regulate T cell function. However, the sources of the ATP that drives this process are not known. We found that stimulation of T cells triggers a spike in cellular ATP production that doubles intracellular ATP levels in <30 s and causes prolonged ATP release into the extracellular space. Cell stimulation triggered rapid mitochondrial Ca(2+) uptake, increased oxidative phosphorylation, a drop in mitochondrial membrane potential (Δψm), and the accumulation of active mitochondria at the immune synapse of stimulated T cells. Inhibition of mitochondria with CCCP, KCN, or rotenone blocked intracellular ATP production, ATP release, intracellular Ca(2+) signaling, induction of the early activation marker CD69, and IL-2 transcription in response to cell stimulation. These findings demonstrate that rapid activation of mitochondrial ATP production fuels the purinergic signaling mechanisms that regulate T cells and define their role in host defense.
authors: From the Departments of Surgery and.
authors: Carola
authors: C
authors: Ledderose
authors: From the Departments of Surgery and.
authors: Yi
authors: Y
authors: Bao
authors: From the Departments of Surgery and Paracelsus Medical University, Salzburg, A-5020, Austria, and.
authors: Markus
authors: M
authors: Lidicky
authors: From the Departments of Surgery and.
authors: Johannes
authors: J
authors: Zipperle
authors: From the Departments of Surgery and.
authors: Linglin
authors: L
authors: Li
authors: From the Departments of Surgery and.
authors: Katharina
authors: K
authors: Strasser
authors: Emergency Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.
authors: Nathan I
authors: NI
authors: Shapiro
authors: From the Departments of Surgery and the Ludwig Boltzmann Institute for Traumatology, Vienna, A-1200, Austria wjunger@bidmc.harvard.edu.
authors: Wolfgang G
authors: WG
authors: Junger
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis / Q000378:metabolism*; D019898:Autocrine Communication; D020013:Calcium Signaling / Q000235:genetics; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000378:metabolism; D003141:Communicable Diseases / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism; D010085:Oxidative Phosphorylation; D011983:Receptors, Purinergic / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D011983:Receptors, Purinergic; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000255:Adenosine Triphosphate
keywords: ATP; Calcium; Cellular Immune Response; Immunosuppression; Infectious Disease; Inflammation; Purinergic Receptor; Purinergic Signaling; T Cell