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Ledderose, Carola

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Ledderose

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Carola

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Ledderose, Carola

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Author's Publications: search.filters.isAuthorOfPublication.eebec9af-6661-4d79-bd62-9395f6962531

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    CD39 Expression Identifies Terminally Exhausted CD8+ T Cells
    (Public Library of Science, 2015) Gupta, Prakash K.; Godec, Jernej; Wolski, David; Adland, Emily; Yates, Kathleen; Pauken, Kristen E.; Cosgrove, Cormac; Ledderose, Carola; Junger, Wolfgang; Robson, Simon; Wherry, E. John; Alter, Galit; Goulder, Philip J. R.; Klenerman, Paul; Sharpe, Arlene; Lauer, Georg; Haining, W. Nicholas
    Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion.
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    mTOR and differential activation of mitochondria orchestrate neutrophil chemotaxis
    (The Rockefeller University Press, 2015) Bao, Yi; Ledderose, Carola; Graf, Amelie F.; Brix, Bianca; Birsak, Theresa; Lee, Albert; Zhang, Jingping; Junger, Wolfgang
    Neutrophils use chemotaxis to locate invading bacteria. Adenosine triphosphate (ATP) release and autocrine purinergic signaling via P2Y2 receptors at the front and A2a receptors at the back of cells regulate chemotaxis. Here, we examined the intracellular mechanisms that control these opposing signaling mechanisms. We found that mitochondria deliver ATP that stimulates P2Y2 receptors in response to chemotactic cues, and that P2Y2 receptors promote mTOR signaling, which augments mitochondrial activity near the front of cells. Blocking mTOR signaling with rapamycin or PP242 or mitochondrial ATP production (e.g., with CCCP) reduced mitochondrial Ca2+ uptake and membrane potential, and impaired cellular ATP release and neutrophil chemotaxis. Autocrine stimulation of A2a receptors causes cyclic adenosine monophosphate accumulation at the back of cells, which inhibits mTOR signaling and mitochondrial activity, resulting in uropod retraction. We conclude that mitochondrial, purinergic, and mTOR signaling regulates neutrophil chemotaxis and may be a pharmacological target in inflammatory diseases.