title: 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.affiliation: Center for Molecular Immunology and Infectious Diseases, Department of Veterinary and Biomedical Sciences and The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Arif A
authors.initials: AA
authors.lastname: Khan
authors.forename: Laura A
authors.initials: LA
authors.lastname: Penny
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Yuzefpolskiy
authors.forename: Surojit
authors.initials: S
authors.lastname: Sarkar
authors.forename: Vandana
authors.initials: V
authors.lastname: Kalia
mesh_terms: D000208:Acute Disease; D000818:Animals; D001117:Arenaviridae Infections / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D049109:Cell Proliferation; D005260:Female; D007156:Immunologic Memory / Q000235:genetics*; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000821:virology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C575895:MIRN17-92 microRNA, mouse; C546843:mTOR protein, mouse; C514862:Akt1 protein, mouse