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Monocytes Regulate the Mechanism of T-cell Death by Inducing Fas-Mediated Apoptosis during Bacterial Infection
Authors:Marc Daigneault  Thushan I. De Silva  Martin A. Bewley  Julie A. Preston  Helen M. Marriott  Andrea M. Mitchell  Timothy J. Mitchell  Robert C. Read  Moira K. B. Whyte  David H. Dockrell
Affiliation:1. Department of Infection and Immunity, University of Sheffield Medical School, Sheffield, United Kingdom.; 2. Sheffield Teaching Hospitals, Sheffield, United Kingdom.; 3. Institute of Microbiology and Infection, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom.;National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States of America
Abstract:Monocytes and T-cells are critical to the host response to acute bacterial infection but monocytes are primarily viewed as amplifying the inflammatory signal. The mechanisms of cell death regulating T-cell numbers at sites of infection are incompletely characterized. T-cell death in cultures of peripheral blood mononuclear cells (PBMC) showed ‘classic’ features of apoptosis following exposure to pneumococci. Conversely, purified CD3+ T-cells cultured with pneumococci demonstrated necrosis with membrane permeabilization. The death of purified CD3+ T-cells was not inhibited by necrostatin, but required the bacterial toxin pneumolysin. Apoptosis of CD3+ T-cells in PBMC cultures required ‘classical’ CD14+ monocytes, which enhanced T-cell activation. CD3+ T-cell death was enhanced in HIV-seropositive individuals. Monocyte-mediated CD3+ T-cell apoptotic death was Fas-dependent both in vitro and in vivo. In the early stages of the T-cell dependent host response to pneumococci reduced Fas ligand mediated T-cell apoptosis was associated with decreased bacterial clearance in the lung and increased bacteremia. In summary monocytes converted pathogen-associated necrosis into Fas-dependent apoptosis and regulated levels of activated T-cells at sites of acute bacterial infection. These changes were associated with enhanced bacterial clearance in the lung and reduced levels of invasive pneumococcal disease.
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