TY - JOUR
T1 - Identifying the initiating events of anti-Listeria responses using mice with conditional loss of IFN-γ receptor subunit 1 (IFNGR1)
AU - Lee, Sang Hun
AU - Carrero, Javier A.
AU - Uppaluri, Ravindra
AU - White, J. Michael
AU - Archambault, Jessica M.
AU - Lai, Koon Siew
AU - Chan, Szeman Ruby
AU - Sheehan, Kathleen C.F.
AU - Unanue, Emil R.
AU - Schreiber, Robert D.
PY - 2013/10/15
Y1 - 2013/10/15
N2 - Although IFN-γis required for resolution of Listeria monocytogenesinfection, 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+ Ifngr1f/f mice with selective IFN-γunresponsiveness in CD8a+ dendritic cells displayed increased susceptibility to infection. This phenotype was due to the inability of IFN-γ-unresponsive CD8a+ dendritic cells to produce the initial burst of IL-12 induced by IFN-γfrom 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 favoringListeriagrowth. Neutralization of IL-4 restoredListeriaresistance inItgax-cre+ Ifngr1f/f mice. We also found thatItgax-cre+ Ifngr1f/f mice survived infection with low-doseListeriaas the result of a second wave of IL-12 produced by Ly6Chi monocytes. Thus, an IFN-γ-driven cascade involving CD8a+ dendritic cells and NK/NKT cells induces the rapid production of IL-12 that initiates the anti-Listeria response.
AB - Although IFN-γis required for resolution of Listeria monocytogenesinfection, 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+ Ifngr1f/f mice with selective IFN-γunresponsiveness in CD8a+ dendritic cells displayed increased susceptibility to infection. This phenotype was due to the inability of IFN-γ-unresponsive CD8a+ dendritic cells to produce the initial burst of IL-12 induced by IFN-γfrom 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 favoringListeriagrowth. Neutralization of IL-4 restoredListeriaresistance inItgax-cre+ Ifngr1f/f mice. We also found thatItgax-cre+ Ifngr1f/f mice survived infection with low-doseListeriaas the result of a second wave of IL-12 produced by Ly6Chi monocytes. Thus, an IFN-γ-driven cascade involving CD8a+ dendritic cells and NK/NKT cells induces the rapid production of IL-12 that initiates the anti-Listeria response.
UR - http://www.scopus.com/inward/record.url?scp=84885449864&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1300910
DO - 10.4049/jimmunol.1300910
M3 - Article
C2 - 24048899
AN - SCOPUS:84885449864
SN - 0022-1767
VL - 191
SP - 4223
EP - 4234
JO - Journal of Immunology
JF - Journal of Immunology
IS - 8
ER -