Bcl11b dose-dependently regulates positive selection of CD8 T cells to the virtual memory fate [ATAC-seq]

Three different genetic models of Bcl11b gene dosage reduction revealed that a <2-fold reduction of Bcl11b protein level redirects CD8 T cell differentiation preferentially to virtual memory fate, at the expense of the naïve compartment. This expanded TVM compartment appeared functionally normal, while remaining naïve CD8 T cells were more sensitive to stimulation.

Timed conditional knockouts and adoptive transfers narrowed the developmental window involved and showed that reduced Bcl11b levels determine diversion to virtual memory fate during intrathymic positive selection. Whereas select target genes were affected, single-cell RNA-seq found that Bcl11b dose primarily controls the flux of thymic precursors to different mature fates. In addition to a modest impact on mitochondrial potential, Bcl11b dose appears to restrict the capacity of cycling CD8SP thymocytes specifically to express a TVM transcriptional program.