Suppression of Cell-Mediated Immunity following Recognition of Phagosome-Confined Bacteria

Abstract

Listeria monocytogenes is a facultative intracellular pathogen capable of inducing a robust cell-mediated immune response to sub-lethal infection. The capacity of L. monocytogenes to escape from the phagosome and enter the host cell cytosol is paramount for the induction of long-lived CD8 T cell–mediated protective immunity. Here, we show that the impaired T cell response to L. monocytogenes confined within a phagosome is not merely a consequence of inefficient antigen presentation, but is the result of direct suppression of the adaptive response. This suppression limited not only the adaptive response to vacuole-confined L. monocytogenes, but negated the response to bacteria within the cytosol. Co-infection with phagosome-confined and cytosolic L. monocytogenes prevented the generation of acquired immunity and limited expansion of antigen-specific T cells relative to the cytosolic L. monocytogenes strain alone. Bacteria confined to a phagosome suppressed the production of pro-inflammatory cytokines and led to the rapid MyD88-dependent production of IL-10. Blockade of the IL-10 receptor or the absence of MyD88 during primary infection restored protective immunity. Our studies demonstrate that the presence of microbes within a phagosome can directly impact the innate and adaptive immune response by antagonizing the signaling pathways necessary for inflammation and the generation of protective CD8 T cells.

T Cell and APC Dynamics In Situ Control the Outcome of Vaccination

“…7. This phenomenon has also recently been observed by the Bahjat et al (82) who show that IL-10 produced by macrophages also plays an inhibitory role during coimmunizations with HKL or other L. monocytogenes mutants that are unable to exit the phagosome. Thus, damage of the MZ and induction of regulatory mechanisms likely work in concert, thus resulting in poor CD8 T cell immunity.…”

Age-related changes in CD8 T cell homeostasis and immunity to infection

“…Of note,the priming of CD8 T cells against Lm is drastically compromised in the absence of either productive intracellular infection of the CD8α+ DC subset[40], or following infection with pathogens unable to escape the phagocytic vacuole into the cytosol [37,41]. Collectively, these data suggest that intracellular pathogen recognition within the CD8α+ DC subset plays an important role in facilitating and/or directing the subsequent priming of effector CD8 T cell populations.…”

“…Sensing of WNV is mediated by pathogen-recognition receptors including TLR3, TLR7/8, and the cytosolic RIG-I-like receptors [44]. Innate sensing of intracellular Lm is also accomplished through TLR/MyD88 pathways, as well as the cytosolic NOD-like receptors (NLR), although MyD88-mediated recognition is dispensable (and perhaps inhibitory) for the development for adaptive immunity to Lm [41,42,45]. …”

Listeria monocytogenes and the Inflammasome: From Cytosolic Bacteriolysis to Tumor Immunotherapy

“…Both Δhly and ΔactA L. monocytogenes mutants are attenuated, however, of these, only ΔactA L. monocytogenes are able to mount a protective cell-mediated immune response (Portnoy et al 1988; Goossens and Milon 1992; Bahjat et al 2009) further highlighting the importance of the cytosol and cytosolic innate immune recognition in stimulating robust CD8 + T-cell mediated immunity.…”