Identifying the Initiating Events of anti-Listeria Responses Using Mice With Conditional Loss of IFN-γ Receptor Subunit 1 (IFNGR1)

J Immunol. 2013 Oct 15;191(8):4223-34. doi: 10.4049/jimmunol.1300910. Epub 2013 Sep 18.

Abstract

Although IFN-γ is required for resolution of Listeria monocytogenes infection, the identities of the IFN-γ-responsive cells that initiate the process remain unclear. We addressed this question using novel mice with conditional loss of IFN-γR (IFNGR1). Itgax-cre(+)Ifngr1(f/f) mice with selective IFN-γ unresponsiveness in CD8α(+) dendritic cells displayed increased susceptibility to infection. This phenotype was due to the inability of IFN-γ-unresponsive CD8α(+) dendritic cells to produce the initial burst of IL-12 induced by IFN-γ from TNF-α-activated NK/NKT cells. The defect in early IL-12 production resulted in increased IL-4 production that established a myeloid cell environment favoring Listeria growth. Neutralization of IL-4 restored Listeria resistance in Itgax-cre(+)Ifngr1(f/f) mice. We also found that Itgax-cre(+)Ifngr1(f/f) mice survived infection with low-dose Listeria as the result of a second wave of IL-12 produced by Ly6C(hi) monocytes. Thus, an IFN-γ-driven cascade involving CD8α(+) dendritic cells and NK/NKT cells induces the rapid production of IL-12 that initiates the anti-Listeria response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Ly / metabolism
  • CD8 Antigens / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Interferon-gamma / immunology*
  • Interleukin-12 / biosynthesis
  • Interleukin-12 / immunology*
  • Interleukin-4 / biosynthesis
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Listeria monocytogenes / immunology*
  • Listeriosis / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Natural Killer T-Cells / immunology
  • Natural Killer T-Cells / metabolism
  • Receptors, Interferon / deficiency
  • Receptors, Interferon / genetics
  • Receptors, Interferon / immunology*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antigens, Ly
  • CD8 Antigens
  • Ly-6C antigen, mouse
  • Receptors, Interferon
  • Tumor Necrosis Factor-alpha
  • interferon gamma receptor
  • Interleukin-12
  • Interleukin-4
  • Interferon-gamma