Late-rising CD4 T cells resolve mouse cytomegalovirus persistent replication in the salivary gland.

Conventional antiviral memory CD4 T cells typically arise during the first two weeks of acute infection. Unlike most viruses, cytomegalovirus (CMV) exhibits an extended persistent replication phase followed by lifelong latency accompanied with some gene expression. We show that during mouse CMV (MCMV) infection, CD4 T cells recognizing an epitope derived from the viral M09 protein only develop after conventional memory T cells have already peaked and contracted. Ablating these CD4 T cells by mutating the M09 genomic epitope in the MCMV Smith strain, or inducing them by introducing the epitope into the K181 strain, resulted in delayed or enhanced control of viral persistence, respectively. These cells were shown to be unique compared to their conventional memory counterparts; producing higher IFNγ and IL-2 and lower IL-10 levels. RNAseq analyses revealed them to express distinct subsets of effector genes as compared to classical CD4 T cells. Additionally, when M09 cells were induced by epitope vaccination they significantly enhanced protection when compared to conventional CD4 T cells alone. These data show that late-rising CD4 T cells are a unique memory subset with excellent protective capacities that display a development program strongly differing from the majority of memory T cells. Author summary: Functional memory T cells are critical to ultimately control chronic viral infection. We show that cytomegalovirus (CMV) induces a population of unique memory CD4 T cells that expand late during infection and resolve viral persistence much better than conventional T memory cells. Mutation of the genomic CMV epitope recognized by these T cells results in markedly enhanced persistent replication, and introduction of the epitope into a CMV strain that lacks it induces much quicker resolution of persistence. When induced via vaccination, we show these T cells provide significantly enhanced protection against acute viral challenge. Together our study identifies a novel population of CD4 T cells that utilize distinct effector function(s) to rapidly resolve persistent viral replication. [ABSTRACT FROM AUTHOR]