Monocytes regulate the mechanism of T-cell death by inducing Fas-mediated apoptosis during bacterial infection

• Published in: PLoS pathogens Vol. 8; no. 7; p. e1002814
• Main Authors: Daigneault, Marc, De Silva, Thushan I, Bewley, Martin A, Preston, Julie A, Marriott, Helen M, Mitchell, Andrea M, Mitchell, Timothy J, Read, Robert C, Whyte, Moira K B, Dockrell, David H
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2012; Public Library of Science (PLoS)
• Subjects: Animals; Apoptosis; Bacteremia; Bacteria; Bacterial infections; Bacterial Proteins; Biology; CD3 Complex - biosynthesis; Cell death; Cells, Cultured; Fas Ligand Protein - metabolism; HIV Infections - immunology; HIV-1 - immunology; Humans; Imidazoles - pharmacology; Immune system; Indoles - pharmacology; Ligands; Lipopolysaccharide Receptors - biosynthesis; Lung - microbiology; Lymphocyte Activation; Lymphocytes; Medicine; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Monocytes - immunology; Monocytes - microbiology; Mortality; Necrosis; Observations; Pneumococcal Infections - immunology; Pneumonia; Properties; Streptococcus infections; Streptococcus pneumoniae - immunology; Streptococcus pneumoniae - pathogenicity; Streptolysins; T cells; T-Lymphocytes - immunology; T-Lymphocytes - microbiology; T-Lymphocytes - physiology; United Kingdom
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1002814

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.