Monocytes Regulate the Mechanism of T-cell Death by Inducing Fas-Mediated Apoptosis during Bacterial Infection

Marc Daigneault,Thushan I De Silva,Martin A Bewley,Andrea M Mitchell,Timothy J Mitchell,Helen M Marriott,Julie A Preston,David H Dockrell,Moira K B Whyte,Robert C Read

doi:10.1371/journal.ppat.1002814

Marc Daigneault, Thushan I De Silva + Show 8 more

Open Access

https://doi.org/10.1371/journal.ppat.1002814

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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.

Highlights

Innate immunity is critical for the rapid recognition and response to pathogenic micro-organisms [1]
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

Summary

Introduction

Innate immunity is critical for the rapid recognition and response to pathogenic micro-organisms [1]. Monocytes are key effectors of the innate immune response to bacteria and contribute to recruitment of T-cells at sites of infection [2]. Other studies have emphasised an important role for CD8+ T-cells during pneumococcal pneumonia by demonstrating CD8+ T-cells limit the extent of the inflammatory response [10]. Despite these observations, CD4+ T-cell inhibition may limit inappropriate degrees of inflammation in some models of pneumococcal infection and improve disease outcome, emphasizing that numbers of T-cell populations must be carefully regulated to ensure effective clearance of bacteria while limiting lung pathology [10,11]

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