Innate IFN-γ is essential for programmed death ligand-1-mediated T cell stimulation following Listeria monocytogenes infection.
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-γ production in mice with combined defects in both IL-12 and type I IFNR negated the impacts of PDL-1 blockade. In turn, IFN-γ ablation using neutralizing Abs or in mice with targeted defects in IFN-γR each eliminated the PDL-1-mediated stimulatory impacts on pathogen-specific T cell expansion. Thus, innate IFN-γ is essential for PDL-1-mediated T cell stimulation.
Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA.
Jared H
JH
Rowe
James M
JM
Ertelt
Sing Sing
SS
Way
D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D000075202:Contraindications; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D018664:Interleukin-12 / Q000172:deficiency / Q000502:physiology; D008088:Listeriosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017471:Receptors, Interferon / Q000172:deficiency / Q000378:metabolism / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D000096743:Interferon gamma Receptor
D057134:Antibodies, Neutralizing; D060890:B7-H1 Antigen; D007371:Interferon-gamma; D018664:Interleukin-12; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C498919:Cd274 protein, mouse