Transcriptome Dynamics Reveals Progressive Transition from Effector to Memory in CD4+ T cells.

Abstract

CD4+ T cells are repositories of immune memory, conferring enhanced immunity to many infectious agents. Studies of acute viral and bacterial infection suggest that memory CD4+ T cells develop directly from effectors. However, delineating these dynamic developmental pathways has been challenging. Here, we used high-resolution single-cell RNA-seq and temporal mixture modelling to examine the fate of Th1 and Tfh effector cells during non-lethal Plasmodium infection in mice. We observed linear Th1 and Tfh pathways towards memory, characterized by progressive halving in the numbers of genes expressed, and partial transcriptomic coalescence. Low-level persisting infection diverted but did not block these pathways. We observed in the Th1-pathway a linear transition from Th1 through a Tr1 state to TEM cells, which were then poised for Th1 re-call. The Tfh-pathway exhibited a modest Th1-signature throughout, with little evidence of Tr1 development, and co-expression of TCM and memory Tfh markers. Thus, we present a high-resolution atlas of transcriptome dynamics for naive to memory transitions in CD4+ T cells. We also defined a subset of memory-associated genes, including transcription factors Id2 and Maf, whose expression increased progressively against the background of transcriptomic quiescence. Single-cell ATAC-seq revealed substantial heterogeneity in chromatin accessibility in single effectors, which was extensively, though incompletely reset and homogenized in memory. Our data reveal that linear transitions from effector to memory occur in a progressive manner over several weeks, suggesting opportunities for manipulating CD4+ T cell memory after primary infection.\n\nHighlightsO_LIscRNA-seq reveals progressive transition from effector to memory in CD4+ T cells.\nC_LIO_LITranscriptome dynamics suggest linear not branching models for memory development.\nC_LIO_LIA subset of genes associates with gradual onset of CD4+ T cell memory.\nC_LIO_LITh1/Tfh predisposition varies among clonotypes with identical antigen-specificity.\nC_LIO_LIscATAC-seq uncovers non-coding \"memory\" elements in the genome.\nC_LI