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

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 micro-RNAs as CD8 T cells differentiate fromnaïve to effector andmemory 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 withwild-type counterparts in the same infectionmilieu-miR-17∼92 deletion resulted in lesser proliferation of antigen-specific cells during primary expansion while favoring enhanced IL-7Ra and Bcl-2 expression and multicytokine polyfunctionality; in contrast, constitutive expression ofmiR-17∼92 promoted terminal effector differentiation, with decreased formation of polyfunctional lymphoidmemory cells. Increased proliferation upon miR-17∼92 overexpression correlatedwith 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.