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

Abstract

SUMMARYThe molecular mechanisms leading to the establishment of durable immunological memory are inadequately understood, limiting the development of effective vaccines and durable anti-tumor immune therapies. Using a T cell-conditional knockout mouse model and a viral pathogen, we show that expression of the transcription cofactor OCA-B (Pou2af1/Bob.1/OBF-1) 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 minimal effects on primary antiviral effector response. Bulk and single-cell gene expression profiling comparing cells transduced with OCA-B and empty vector at primary effector response identifies changes in gene expression consistent with later memory formation, including genes increased (Tbx21, Il7r, Gadd45b, Socs2) in specific subpopulations by ectopic OCA-B expression. Short-lived effector T cell compartments are expanded but show increased expression of Gadd45b and Socs2, while clusters of effector cells with memory potential show increased expression of Bcl2, Il7r, Tcf7 and Slamf6. We also describe an OCA-B-mCherry reporter mouse allele that selectively labels B and T lymphocytes, and shows high reporter expression in CD4+ TCM cells. We show that elevated OCA-B expression prospectively identifies cells with increased survival capability and memory recall potential. Cumulatively, the results demonstrate that OCA-B is necessary and sufficient to promote CD4 T cell memory in vivo.In brief eTOC blurbSun et al. use T cell conditional knockout and ectopic expression to show that OCA-B is required for, and sufficient to promote, CD4+ memory T cell formation in vivo. Using fluorescent reporter mice, they show that OCA-B expression can be used to prospectively identify effector T cells with enhanced memory potential.HighlightsEctopic OCA-B expression is sufficient to promote Th1 memoryOCA-B controls the expression of genes in responding CD4+ T cells that regulate effector response and memoryOCA-B expression can be used to prospectively identify CD4+ memory precursor cellsOCA-B expression is reduced after memory cells are formed