title: Monocytes regulate the mechanism of T-cell death by inducing Fas-mediated apoptosis during bacterial infection.
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.
authors: Department of Infection and Immunity, University of Sheffield Medical School, Sheffield, United Kingdom.
authors: Marc
authors: M
authors: Daigneault
authors: Thushan I
authors: TI
authors: De Silva
authors: Martin A
authors: MA
authors: Bewley
authors: Julie A
authors: JA
authors: Preston
authors: Helen M
authors: HM
authors: Marriott
authors: Andrea M
authors: AM
authors: Mitchell
authors: Timothy J
authors: TJ
authors: Mitchell
authors: Robert C
authors: RC
authors: Read
authors: Moira K B
authors: MK
authors: Whyte
authors: David H
authors: DH
authors: Dockrell
mesh_terms: D000818:Animals; D017209:Apoptosis; D016470:Bacteremia; D001426:Bacterial Proteins; D017252:CD3 Complex / Q000096:biosynthesis; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008168:Lung / Q000382:microbiology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology* / Q000382:microbiology; D009336:Necrosis; D011008:Pneumococcal Infections / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000276:immunology / Q000472:pathogenicity; D013301:Streptolysins; D013601:T-Lymphocytes / Q000276:immunology / Q000382:microbiology / Q000502:physiology*
chemical_list: D001426:Bacterial Proteins; D017252:CD3 Complex; D053222:Fas Ligand Protein; D007093:Imidazoles; D007211:Indoles; D018950:Lipopolysaccharide Receptors; D013301:Streptolysins; C507699:necrostatin-1; C032290:plY protein, Streptococcus pneumoniae