Differential requirement for IRF4 in CD8+ T cell responses to acute versus chronic LCMV infection (IRM4P.498)

Abstract

Abstract The magnitude of the CD8+ T cell response to acute infection is regulated by the strength of TCR signaling. A key component to this is the level of expression of the transcription factor IRF4, which controls CD8+ T cell expansion in a dose-dependent manner. During an acute response to LCMV-Armstrong, a modest reduction in IRF4 levels, such as that achieved by a haplo-deficiency at the irf4 locus, leads to a 2-4 fold reduction in the number of LCMV specific CD8+ T cells without impacting viral clearance (RN manuscript submitted). These data indicate that acute LCMV infections are associated with an expansion of cognate CD8+ T cells that is in excess of that needed to clear the virus. In contrast, during LCMV-clone 13 infection, the modestly-reduced CD8+ T cell response of irf4+/- T cells fails to control the infection, resulting in long-term viral persistence. In this system, loss of one allele of irf4 results in reduced CD8+ T cell function, increased exhaustion due to loss of PD1 low Tbet high precursors, and less weight loss than in LCMV-clone 13-infected WT mice. These data indicate differential requirements for high levels of IRF4 in generating functional CD8+ T cell responses capable of clearing acute versus chronic virus infections.