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Innate IFN-? is essential for programmed death ligand-1-mediated T cell stimulation following Listeria monocytogenes infection.

ABSTRACT: Although best characterized for sustaining T cell exhaustion during persistent viral infection, programmed death ligand-1 (PDL-1) also stimulates the expansion of protective T cells after infection with intracellular bacterial pathogens. Therefore, establishing the molecular signals that control whether PDL-1 stimulates immune suppression or activation is important as immune modulation therapies based on manipulating PDL-1 are being developed. In this study, the requirement for PDL-1 blockade initiated before infection with the intracellular bacterium Listeria monocytogenes in reducing pathogen-specific T cell expansion is demonstrated. In turn, the role of proinflammatory cytokines triggered early after L. monocytogenes infection in controlling PDL-1-mediated T cell stimulation was investigated using mice with targeted defects in specific cytokines or cytokine receptors. These experiments illustrate an essential role for IL-12 or type I IFNs in PDL-1-mediated expansion of pathogen-specific CD8(+) T cells. Unexpectedly, direct stimulation by neither IL-12 nor type I IFNs on pathogen-specific CD8(+) cells was essential for PDL-1-mediated expansion. Instead, the absence of early innate IFN-? production in mice with combined defects in both IL-12 and type I IFNR negated the impacts of PDL-1 blockade. In turn, IFN-? ablation using neutralizing Abs or in mice with targeted defects in IFN-?R each eliminated the PDL-1-mediated stimulatory impacts on pathogen-specific T cell expansion. Thus, innate IFN-? is essential for PDL-1-mediated T cell stimulation.

SUBMITTER: Rowe JH

PROVIDER: S-EPMC3402342 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Innate IFN-γ is essential for programmed death ligand-1-mediated T cell stimulation following Listeria monocytogenes infection.

Rowe Jared H JH Ertelt James M JM Way Sing Sing SS

Journal of immunology (Baltimore, Md. : 1950) 20120618 2

Although best characterized for sustaining T cell exhaustion during persistent viral infection, programmed death ligand-1 (PDL-1) also stimulates the expansion of protective T cells after infection with intracellular bacterial pathogens. Therefore, establishing the molecular signals that control whether PDL-1 stimulates immune suppression or activation is important as immune modulation therapies based on manipulating PDL-1 are being developed. In this study, the requirement for PDL-1 blockade in ...[more]

PMID: 22711893

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Project description:MicroRNA (miR) miR-155 modulates microglial activation and polarization, but its role in activation of microglia during bacterial brain infection is unclear. We studied miR-155 expression in brains of C57BL/6 (B6.WT) mice infected i.p. with the neuro-invasive bacterial pathogen Listeria monocytogenes (L. monocytogenes). Infected mice were treated with ampicillin starting 2 days (d) post-infection (p.i.) and analyzed 3d, 7d, and 14d p.i. Virulent L. monocytogenes strains EGD and 10403s upregulated miR-155 in whole brain 7 d p.i. whereas infection with avirulent, non-neurotropic ?hly or ?actA L. monocytogenes mutants did not. Similarly, infection with virulent but not mutated bacteria upregulated IFN-? mRNA in the brain at 7 d p.i. Upregulation of miR-155 in microglia was confirmed by qPCR of flow cytometry-sorted CD45intCD11bpos brain cells. Subsequently, brain leukocyte influxes and gene expression in sorted microglia were compared in L. monocytogenes-infected B6.WT and B6.Cg-Mir155tm1.1Rsky/J (B6.miR-155-/-) mice. Brain influxes of Ly-6Chigh monocytes and upregulation of IFN-related genes in microglia were similar to B6.WT mice at 3 d p.i. In contrast, by d 7 p.i. expressions of microglial IFN-related genes, including markers of M1 polarization, were significantly lower in B6.miR-155-/- mice and by 14 d p.i., influxes of activated T-lymphocytes were markedly reduced. Notably, CD45highCD11bpos brain cells from B6.miR-155-/- mice isolated at 7 d p.i. expressed 2-fold fewer IFN-? transcripts than did cells from B6.WT mice suggesting reduced IFN-? stimulation contributed to dampened gene expression in B6.miR-155-/- microglia. Lastly, in vitro stimulation of 7 d p.i. brain cells with heat-killed L. monocytogenes induced greater production of TNF in B6.miR-155-/- microglia than in B6.WT microglia. Thus, miR-155 affects brain inflammation by multiple mechanisms during neuroinvasive L. monocytogenes infection. Peripheral miR-155 promotes brain inflammation through its required role in optimal development of IFN-?-secreting lymphocytes that enter the brain and activate microglia. Microglial miR-155 promotes M1 polarization, and also inhibits inflammatory responses to stimulation by heat-killed L. monocytogenes, perhaps by targeting Tab2.

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Innate IFN-? is essential for programmed death ligand-1-mediated T cell stimulation following Listeria monocytogenes infection.

Publications

Innate IFN-γ is essential for programmed death ligand-1-mediated T cell stimulation following Listeria monocytogenes infection.

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