TLR-independent neutrophil-derived IFN-γ is important for host resistance to intracellular pathogens

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 26; pp. 10711 - 10716
• Main Authors: Sturge, Carolyn R., Benson, Alicia, Raetz, Megan, Wilhelm, Cara L., Mirpuri, Julie, Vitetta, Ellen S., Yarovinsky, Felix
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.06.2013; National Acad Sciences
• Subjects: Animals; Biological Sciences; Cell lines; Host-Parasite Interactions - immunology; Host-Pathogen Interactions - immunology; Immunity, Innate; Infections; Interferon-gamma - deficiency; Interferon-gamma - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Natural killer cells; Natural killer T cells; Neutrophils; Neutrophils - immunology; Neutrophils - metabolism; Parasite hosts; Parasites; Pathogens; Salmonella typhimurium - immunology; Salmonella typhimurium - pathogenicity; T lymphocytes; T-Lymphocytes - immunology; Toll-Like Receptors - deficiency; Toll-Like Receptors - genetics; Toll-Like Receptors - immunology; Toxoplasma - immunology; Toxoplasma - pathogenicity; innate immunity; host defense
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1307868110

IFN-γ is a major cytokine that is critical for host resistance to a broad range of intracellular pathogens. Production of IFN-γ by natural killer and T cells is initiated by the recognition of pathogens by Toll-like receptors (TLRs). In an experimental model of toxoplasmosis, we have identified the presence of a nonlymphoid source of IFN-γ that was particularly evident in the absence of TLR-mediated recognition of Toxoplasma gondii . Genetically altered mice lacking all lymphoid cells due to deficiencies in Recombination Activating Gene 2 and IL-2Rγ c genes also produced IFN-γ in response to the protozoan parasite. Flow-cytometry and morphological examinations of non-NK/non-T IFN-γ ⁺ cells identified neutrophils as the cell type capable of producing IFN-γ. Selective elimination of neutrophils in TLR11 ⁻/⁻ mice infected with the parasite resulted in acute susceptibility similar to that observed in IFN-γ–deficient mice. Similarly, Salmonella typhimurium infection of TLR-deficient mice induces the appearance of IFN-γ ⁺ neutrophils. Thus, neutrophils are a crucial source for IFN-γ that is required for TLR-independent host protection against intracellular pathogens.