Neutrophil-Derived IFN-γ in Toxoplasma gondii Infection and Innate Immunity

Abstract

Interferon-gamma (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 (NK) and T cells is initiated by the recognition of pathogens through Toll-like receptors (TLRs). In an experimental model of toxoplasmosis we have identified the presence of a non-lymphoid source of IFN-γ that was particularly evident in the absence of TLR-mediated recognition of Toxoplasma gondii. Flow-cytometry and morphological examinations of non-NK/non-T IFN-γ-positive 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. These data show that neutrophils are a biologically significant source of IFN-γ during T. gondii infection. Additionally, we investigated the role of neutrophil IFN-γ in another intracellular infection, Salmonella typhimurium, and found that neutrophils were also IFN-γ-positive. Examination of neutrophils in different locations in a mouse model revealed that they all expressed low amounts of IFN-γ regardless of infection status. In particular, the bone marrow niche contained an IFN-γ+ population that was negative for the Ly-6G marker characteristic of mature neutrophils in peripheral tissues. Recent work defining neutrophil developmental stages by flow-cytometry allowed us to discern that precursor neutrophils at the promyelocyte stage (Ly-6G negative) were positive for IFN-γ. Furthermore, neutrophil-derived IFN-γ was prestored in granules during neutrophil lineage development although the mechanisms behind this phenomena are not yet understood. This work, combined with the recent work of other laboratories, suggests that neutrophils can have defined phenotypes and cytokine production similar to that of T cells or Innate Lymphoid cells (ILCs). These findings have broad implications for all disease states where neutrophils are the first responders to infections.