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

作者：Khan Arif A; Penny Laura A; Yuzefpolskiy Yevgeniy; Sarkar Surojit; Kalia Vandana^*

来源：Blood, 2013, 121(22): 4473-4483.

DOI：10.1182/blood-2012-06-435412

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 naive to effector and memory states, with short-lived effectors transiently expressing higher levels of oncogenic miR-17 similar to 92 compared with the relatively less proliferating memory-fated effectors. Conditional CD8 T-cell-intrinsic gain or loss of expression of miR-17 similar to 92 in mature cells after activation resulted in striking reciprocal effects compared with wild-type counterparts in the same infection milieu-miR-17 similar to 92 deletion resulted in lesser proliferation of antigen-specific cells during primary expansion while favoring enhanced IL-7R alpha and Bcl-2 expression and multicytokine polyfunctionality; in contrast, constitutive expression of miR-17 similar to 92 promoted terminal effector differentiation, with decreased formation of polyfunctional lymphoid memory cells. Increased proliferation upon miR-17 similar to 92 overexpression correlated with decreased expression of tumor suppressor PTEN and increased PI3K-AKT-mTOR signaling. Thus, these studies identify miR17 similar to 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 similar to 92 as a potential target for modulating immunologic outcome after vaccination or immunotherapeutic treatments of cancer, chronic infections, or autoimmune disorders.

• 出版日期2013-5-30