Identifying the initiating events of anti-Listeria responses using mice with conditional loss of IFN-γ receptor subunit 1 (IFNGR1).
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.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
Sang Hun
SH
Lee
Javier A
JA
Carrero
Ravindra
R
Uppaluri
J Michael
JM
White
Jessica M
JM
Archambault
Koon Siew
KS
Lai
Szeman Ruby
SR
Chan
Kathleen C F
KC
Sheehan
Emil R
ER
Unanue
Robert D
RD
Schreiber
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology*; D015847:Interleukin-4 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000096743:Interferon gamma Receptor
D000950:Antigens, Ly; D016827:CD8 Antigens; D007371:Interferon-gamma; D018664:Interleukin-12; D015847:Interleukin-4; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C494192:Ly-6C antigen, mouse