Microbial exposure expands a Ly6C+ subpopulation of long lived naive CD8 T cells with a rapid effector function via type I intereferons

Abstract

Abstract Previously we have described human ‘memory T cells with a naïve phenotype’ which were increased in human subjects recovering from acute West Nile Virus infection (Pulko et al., Nature Immunology, 2016). These cells had a naïve phenotype but exhibited some signs of basal activation and displayed a rapid effector function upon polyclonal stimulation. These findings in humans prompted us to investigate effects of bystander infections on naïve CD8 T cells in mice, and here we have utilized viral (West Nile Virus) and bacterial (Listeria monocytogenes) models but most importantly we investigated naïve T cells under non specific pathogen free (SPF) conditions in B6 mice cohoused with pet shop mice hosting a variety of infections. We describe a novel population of naïve CD8 T cells characterized by expression of a single memory marker Ly6C with similar properties to human ‘memory T cells with a naïve phenotype’. Under basal conditions Ly6C is expressed on ~20% on naïve T cells and is transiently up regulated during acute infection but only on CD5hi cells with higher affinity for self peptide-MHC I complexes. Under conditions of ‘non SPF microbiome’ this population is expanded long term and enriched in the lymph nodes. We show that Ly6C+ naïve CD8s are enriched in the lymph nodes and receive improved homeostatic signals from lymph node stromal cells which lead to upregulation of survival factors such as BCL-2 and extend the lifespan of Ly6C+ cells. Our mechanistic studies have identified type I interferons as the only inflammatory signal required for the induction of this population. However this effect is partially indirect as type I interferon induced expression of Ly6C on CD8 T cells is prevented by MHC I blockade.