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 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.

• Authors: Arif A Khan, Laura A Penny, Yevgeniy Yuzefpolskiy, Surojit Sarkar, Vandana Kalia
• Journal: Blood (Blood) Vol. 121 Issue 22 Pg. 4473-83 (May 30 2013) ISSN: 1528-0020 [Electronic] United States
• PMID: 23596046 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MIRN17-92 microRNA, mouse
• MicroRNAs
• mTOR protein, mouse
• Akt1 protein, mouse
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Acute Disease
• Animals
• Arenaviridae Infections (genetics, immunology)
• CD8-Positive T-Lymphocytes (cytology, immunology, virology)
• Cell Differentiation (immunology)
• Cell Lineage (immunology)
• Cell Proliferation
• Female
• Immunologic Memory (genetics)
• Lymphocytic Choriomeningitis (genetics, immunology)
• Lymphocytic choriomeningitis virus
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs (genetics, immunology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (immunology)
• T-Lymphocyte Subsets (cytology, immunology, virology)
• TOR Serine-Threonine Kinases (metabolism)
• Transcription, Genetic (immunology)
• Up-Regulation (immunology)