CD8 T cell fate is programmed by a miRNA-mediated mechanism

Abstract

Abstract CD8 T cells are the cytotoxic effectors of the adaptive immune response, clearing virally infected and cancerous cells within the host. CD8 T cells acquire their cytotoxic function by differentiating into cytotoxic T lymphocytes (CTLs). Once the CTLs have cleared the antigen, the majority of responding cells will die during contraction, while a small population of the antigen-specific responders will remain, differentiating into long-lived memory cells that provide potent protection to the host upon re-encounter with the antigen. However, during chronic infection and cancer, CD8 T cells are often diverted into the so-called exhausted state, in which CTLs are losing their function. As such, the ability to program the differentiation of CD8 T cells into a particular lineage is an important therapeutic strategy. We have identified a global post-transcriptional mechanism that directs the fate of differentiating CD8 T cells. Specifically, we have found that let-7 miRNAs are downregulated upon T cell activation, allowing T cells to differentiate into CTLs. Moreover, we have found that prolonged expression of these miRNAs programs CD8 T cells to become memory cells, while complete loss induces exhaustion. Thus, these findings may have important implications for the improvement of current immunotherapies targeting CD8 T cell fate.