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

Abstract

Virtual memory T cells are increasingly recognized as a functionally distinct lineage within the CD8 T cell pool, but when and how commitment to the lineage is enforced remain poorly understood. Here we demonstrate that TVM lineage choice is exceptionally sensitive to dosage and repression competence of the key T cell transcription factor Bcl11b. Three different genetic models of slightly reduced Bcl11b each biased CD8 cell development to TVM generation without deregulating effector differentiation. Timed conditional knockouts and adoptive transfers narrowed the developmental window and showed that Bcl11b levels determine diversion to virtual memory fate uniquely during intrathymic positive selection. Whereas total Bcl11b loss disrupts TCR signalling, a <2-fold dose reduction of Bcl11b enhanced selective responses to TCR stimulation. Chromatin accessibility profiling and single cell RNA-seq indicated that Bcl11b dose reduction redirects cells to the TVM fate, from the late cycling fraction of mature CD8SP thymocytes, by a mechanism independent of previously described cytokine-driven pathways.