LOW-AFFINITY CYTOTOXIC T-LYMPHOCYTES REQUIRE IFN-GAMMA TO CLEAR AN ACUTE VIRAL-INFECTION

The majority of the response of cytotoxic T-lymphocytes (CTL) to lymph ocytic choriomeningitis virus (LCMV) in H-2(d) mice is directed toward one epitope located on the nucleoprotein (NP, aa 118-126), and usuall y no primary responses to other epitopes are detectable. Previous stud ies have shown that thymic expression of lymphocytic choriomeningitis virus-nucleoprotein (LCMV-NP) in H-2(d) transgenic mice (Thy-NP mice) leads to deletion of high-affinity anti-LCMV-NP CTL by negative select ion. Selection is incomplete, so that low-affinity NP-specific CTL pas s through the thymus and are delectable in the periphery. To analyze t he importance of interferon-gamma (IFN-gamma) in the ability of low-af finity antiviral CTL to clear an acute viral infection, double transge nic mice were generated that are IFN-gamma deficient and express the N P of LCMV in the thymus (Thy-NP x IFN-gamma-/-mice). When infected wit h LCMV, these bigenic mice were unable to clear the infection despite generating low-affinity primary antiviral CTL, and they became persist ently infected. In contrast, IFN-gamma competent Thy-NP mice cleared L CMV within 7-8 days and IFN-gamma deficient mice that did not express NP in their thymus generated high-affinity CTL that terminated an acut e LCMV infection within 10-12 days post-viral challenge. Persistently infected IFN-gamma deficient mice selectively depleted LCMV-specific C TL and displayed reduced levels of antigen-presenting cells in the spl een, and 60% of these mice died at 2-3 months postinfection. Thus, IFN -gamma is required for clearing an acute viral infection in the absenc e of a high-affinity CTL response. In the absence of IFN-gamma persist ent viral infection results despite the presence Of low-affinity CTL. (C) 1997 Academic Press.