Crucial role of FOXO1 in inflationary CD8+ T-cell responses during persistent viral infection

Abstract

Abstract Cytomegalovirus (CMV) establish persistent infection that induce the accumulation of virus-specific T cells over time in a process called memory inflation. Although persistence of antigen (Ag) is considered essential, the molecular pathway for the inflationary T-cell development is poorly understood. Mainly, inflationary CD8 T-cells have an effector-memory phenotype (KLRG1hi CD27−), but a low percentage of them express a central-memory phenotype (KLRG1lo CD27+), which are considered as their memory precursors. To study the role of FOXO1 in CD8 T cells during a persistent viral infection, we analyzed mouse bone marrow chimeras in which FOXO1 was specifically deleted in CD8 T cells. These mice were infected with MCMV-Δm157 strain, and the expansion and phenotype of inflationary and acute-contracting T cells was examined. The results revealed that the IE3 and M38 CD8 T cell responses do not inflate in absence of FOXO1. Furthermore, with an absence of FOXO1, there were fewer Ag-specific CD8 T cells that produced both IFNγ and TNFα. Consistent with this lack of CD8 effector cells the mice were less able to control the virus in the spleen and the liver at day 6 after infection. Moreover, we found that FOXO1 KO Ag-specific CD8 T cells fail to up-regulate the memory associated transcription factors, TCF-1 and EOMES, correlating with a lower percentage of memory precursors (KLRG1lo CD27+). Finally, we found that FOXO1 KO Ag-specific CD8 T cells cycle normally (Ki67+), but display an anergic state, as measured by calcium mobilization activation, and are prone to apoptosis. Collectively, these results demonstrate an intrinsic role for FOXO1 in establishing the inflationary memory program that is essential to forming long-lived effector memory cells