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

著者 Stelekati E , Chen Z , Manne S , Kurachi M , Ali MA , Lewy K , Cai Z , Nzingha K , McLane LM , Hope JL , Fike AJ , Katsikis PD , Wherry EJ
Cell Rep.2018 May 15 ; 23(7):2142-2156.
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Persistent viral infections and tumors drive development of exhausted T (T) cells. In these settings, T cells establish an important host-pathogen or host-tumor stalemate. However, T cells erode over time, leading to loss of pathogen or cancer containment. We identified microRNA (miR)-155 as a key regulator of sustained T 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 cells. However, rather than strictly antagonizing exhaustion, miR-155 promoted a terminal T 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 cells. Thus, we identify a mechanism of miR-155 regulation of T cells and a key role for Fosl2 in T cell exhaustion.
PMID: 29768211 [PubMed - in process]
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