IFN-γ plays an essential role in NK-induced CD8⁺ responses. (A) In vivo IFN-γ blockade leads to outgrowth of Ag104L^d LIGHT tumor at the primary tumor challenge. C3B6F1 mice were subcutaneously inoculated with Ag104L^d LIGHT tumor cells and treated twice weekly with anti–IFN-γ antibody or control anti–rat Ig for 2 weeks. (B) Blocking IFN-γ causes tumor growth at the secondary tumor challenge. The C3B6F1 mice were subcutaneously inoculated with 1 × 10⁷ Ag104L^d tumor cells after 40 days of primary Ag104L^d LIGHT tumor rejection and treated with anti–IFN-γ antibody or control anti–rat Ig as previously described. (C) IFN-γ blockade impairs NK cell–induced CD8⁺ cell proliferation. rLIGHT-preactivated NK cells from Rag-1^-/- mice were incubated with the culture of 2C T and irradiated Ag104L^d cells with different doses of anti–IFN-γ antibody or 100 ng/mL rIFN-γ for 7 days. ³H-TdR incorporation and specific lysis assays were performed as previously described. (D) IFN-γ–deficient mice impair NK cell–induced CD8⁺ proliferation and lytic activity. rLIGHT-preactivated NK cells from Rag1^-/- or Ifng^-/- mice were added to the culture of 2C T and irradiated Ag104L^d cells at days 0, 3, and 5 for 7 days. NK cells from Ifng^-/- mice showed reduced responses (P < .01). rIFN-γ was added to the culture of Ifng^-/- NK cells at the indicated times. Data analysis was performed by using the Student t test. Averaged results are expressed as mean plus or minus SD.