Long-Term Persistence of Exhausted CD8 T Cells in Chronic Infection Is Regulated by MicroRNA-155

Persistent viral infections and tumors drive development of exhausted T (T_EX) cells. In these settings, T_EX cells establish an important host-pathogen or host-tumor stalemate. However, T_EX cells erode over time, leading to loss of pathogen or cancer containment. We identified microRNA (miR)-155 as a key regulator of sustained T_EX cell responses during chronic lymphocytic choriomeningitis virus (LCMV) infection. Genetic deficiency of miR-155 ablated CD8 T cell responses during chronic infection. Conversely, enhanced miR-155 expression promoted expansion and long-term persistence of T_EX cells. However, rather than strictly antagonizing exhaustion, miR-155 promoted a terminal T_EX cell subset. Transcriptional profiling identified coordinated control of cell signaling and transcription factor pathways, including the key AP-1 family member Fosl2. Overexpression of Fosl2 reversed the miR-155 effects, identifying a link between miR-155 and the AP-1 transcriptional program in regulating T_EX cells. Thus, we identify a mechanism of miR-155 regulation of T_EX cells and a key role for Fosl2 in T cell exhaustion.