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.

Author Summary

T-cells are important contributors to the early host response to pneumonia, but their numbers must be tightly regulated to limit inflammatory lung injury. Cell death regulates T-cell numbers but the mechanism of execution influences the inflammatory cost with apoptosis viewed as predominantly anti-inflammatory and necrosis as pro-inflammatory. We show that monocytes determine the mechanism of T-cell death during acute bacterial infection. Monocytes triggered Fas-dependent T-cell apoptosis but in the absence of monocytes T-cells died by necrosis, which required the pneumococcal virulence factor pneumolysin. We also show that Fas ligand is required to regulate the early T-cell dependent host response to pneumococci during pneumonia. Although monocytes have previously been associated with enhancement of the inflammatory response our results imply that a key role of monocytes is to dampen the inflammatory response through induction of Fas-mediated apoptosis of activated T-cells during S. pneumoniae pneumonia. Our data identifies a critical and unrecognized regulatory role for monocytes during pneumonia.