Late-rising CD4 T cells show dramatic control of cytomegalovirus persistence

Abstract

Abstract Conventional CD4 T cells typically expand and establish memory pools within the first few weeks of acute viral infection. However, cytomegalovirus (CMV) exhibits an extended persistent replication phase followed by lifelong latency, suggesting the induction, phenotype and/or function of protective memory CD4 T cells may differ. We show that during CMV infection in mice, CD4 T cells recognizing an epitope derived from the viral M09 protein develop long after conventional memory T cells have already formed. These cells are unique compared to their conventional memory counterparts; showing high IFNγ and IL-2 production at times of viral persistence. Ablating these CD4 T cells by mutating the M09 genomic epitope, or inducing them through vaccination, revealed them far superior at resolving persistent replication. RNAseq data reveal that these ‘late-rising’ and conventional CD4 T cells differ dramatically in their transcriptional signatures, and that M09 cells show a uniquely restricted T cell receptor repertoire. We believe these results may help instruct CMV vaccine and cellular immunotherapy approaches in people, and will also provide a blueprint for determining whether similar late-rising CD4 T cells exist in other chronic virus infections.