Transcription coactivator OCA-B/Pou2af1 is necessary and sufficient to promote T cell-intrinsic CD4 memory

Abstract

Abstract The establishment of durable immunological memory remains a poorly understood aspect of lymphocyte biology and a limiting factor in vaccine development. Using a T cell-conditional OCA-B (Pou2af1) knockout model and a mouse viral pathogen, we show that expression of the transcription cofactor OCA-B within T cells is necessary for proper CD4+ memory T cell formation. We also show that ectopic OCA-B expression is sufficient to drive T cells towards a memory fate while having no effect on primary antiviral effector response. Bulk and single-cell gene expression profiling comparing cells transduced with OCA-B and empty vector at peak primary viral response identifies changes in gene expression consistent with later memory formation. Intersecting differentially expressed genes in bulk RNA-seq with prior ChIP-seq identifies direct targets increased (Tbx21, Zeb2, Gadd45b, Socs2) and decreased (Zbtb16, Ccr1) by ectopic OCA-B expression. Single-cell RNA-seq reveals expansion of short-lived effector T cell compartments with increased expression of Gadd45b and Socs2, as well as increased expression of memory-associated genes such as Slamf6, Il7r and Tcf1 in smaller clusters of effector cells with memory potential. We also describe a new OCA-B-mCherry reporter mouse that efficiently labels B and T lymphocytes and that shows high expression in CD4+ TCM cells. Cumulatively, the results demonstrate that OCA-B expression in T cells is necessary and sufficient to promote CD4 T cell memory in vivo. Supported by grants from NIH (R01 AI100873)