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

Abstract

SUMMARY Persistent viral infections and tumors drive development of exhausted T (TEX) cells. In these settings, TEX cells establish an important host-pathogen or host-tumor stalemate. However, TEX cells erode over time, leading to loss of pathogen or cancer containment. We identified microRNA (miR)-155 as a key regulator of sustained TEX 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 TEX cells. However, rather than strictly antagonizing exhaustion, miR-155 promoted a terminal TEX 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 TEX cells. Thus, we identify a mechanism of miR-155 regulation of TEX cells and a key role for Fosl2 in T cell exhaustion.

Immune Profiling of Atherosclerotic Plaques Identifies Innate and Adaptive Dysregulations Associated with Ischemic Cerebrovascular Events

“…Plaque-specific clusters 1, 3, and 9 uniquely upregulated signaling associated with activation-induced T cell exhaustion, including PKCθ signaling, required for TCR-induced T cell activation 71 , and NFAT signaling 72,73 . Overall, these data confirm our CyTOF observations that in blood, T cells display a quiescent state, while in plaques, they exhibit distinct degrees of activation which overlaps with exhaustion, suggesting the stepwise and progressive loss of T-cell functions in response to chronic, persistent inflammation 55–57,74 . A sub analysis of individual CD4 + and CD8 + T cells across blood and plaque is available as Supplementary Information ( Supplementary Fig.…”

“…6e ), suggesting that these highly activated cells initiate a parallel exhaustion reprogramming. Because T cell exhaustion is characterized by the gradual and continuous depletion of effector functions in response to chronic, non-resolving inflammation 55–57,74,89 , the identification of concomitant activation and exhaustion signaling suggests that these activated cells initiate exhaustion reprogramming.…”

Chimeric antigen receptor T cell persistence and memory cell formation

“…The discrete expression of different miRNA subsets in different memory and effector T cell subsets imparts critical control over natural gene sets involved in the broad function of each subset. miR‐155 is expressed in T EM and T E and controls multiple points of protein expression to enhance Th1 and Th17 inflammation . An attractive proposition in adoptive cell therapy is the avoidance of preconditioning with lymphodepletion regimes that may cause adverse events, mostly related to toxicity and immunosuppression.…”

“…Despite possessing limited capacity for selfrenewal, improving T E longevity would be expected to improve anti-cancer immunity. 13,31…”

“…miR-155 is expressed in T EM and T E and controls multiple points of protein expression to enhance Th1 and Th17 inflammation. 20,31 An attractive proposition in adoptive cell therapy is the avoidance of preconditioning with lymphodepletion regimes that may cause adverse events, mostly related to toxicity and immunosuppression. However, lymphodepletion reduces competition for endogenous host common c-chain cytokines required for the proliferation and maintenance of adoptively transferred lymphocytes.…”