MicroRNA-17∼ 92 regulates effector and memory CD8 T-cell fates by modulating proliferation in response to infections

AA Khan, LA Penny, Y Yuzefpolskiy… - Blood, The Journal …, 2013 - ashpublications.org
Blood, The Journal of the American Society of Hematology, 2013ashpublications.org
The precise microRNAs and their target cellular processes involved in generation of durable
T-cell immunity remain undefined. Here we show a dynamic regulation of microRNAs as
CD8 T cells differentiate from naïve to effector and memory states, with short-lived effectors
transiently expressing higher levels of oncogenic miR-17∼ 92 compared with the relatively
less proliferating memory-fated effectors. Conditional CD8 T-cell–intrinsic gain or loss of
expression of miR-17∼ 92 in mature cells after activation resulted in striking reciprocal …
Abstract
The precise microRNAs and their target cellular processes involved in generation of durable T-cell immunity remain undefined. Here we show a dynamic regulation of microRNAs as CD8 T cells differentiate from naïve to effector and memory states, with short-lived effectors transiently expressing higher levels of oncogenic miR-17∼92 compared with the relatively less proliferating memory-fated effectors. Conditional CD8 T-cell–intrinsic gain or loss of expression of miR-17∼92 in mature cells after activation resulted in striking reciprocal effects compared with wild-type counterparts in the same infection milieu—miR-17∼92 deletion resulted in lesser proliferation of antigen-specific cells during primary expansion while favoring enhanced IL-7Rα and Bcl-2 expression and multicytokine polyfunctionality; in contrast, constitutive expression of miR-17∼92 promoted terminal effector differentiation, with decreased formation of polyfunctional lymphoid memory cells. Increased proliferation upon miR-17∼92 overexpression correlated with decreased expression of tumor suppressor PTEN and increased PI3K-AKT-mTOR signaling. Thus, these studies identify miR17∼92 as a critical regulator of CD8 T-cell expansion and effector and memory lineages in the physiological context of acute infection, and present miR-17∼92 as a potential target for modulating immunologic outcome after vaccination or immunotherapeutic treatments of cancer, chronic infections, or autoimmune disorders.
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