title: Dicer controls CD8+ T-cell activation, migration, and survival.
abstract: The RNaseIII enzyme Dicer is required for mature microRNA production. Although extensive investigation has been carried out to determine the role of Dicer/miRNAs in the immune system, their function in mature CD8(+) T cells has not been examined. We deleted Dicer in mature polyclonal and TCR transgenic CD8(+) T cells using either tat-cre or the distal lck promoter, which drives cre expression after the stage of positive selection. Following antigenic challenge by a pathogen infection in vivo, Dicer-deleted CD8(+) T cells failed to accumulate at the usual peak of the response. Surprisingly however, we found that deletion of Dicer in mature CD8(+) T cells allowed them to respond more rapidly than control cells to TCR stimuli in vitro. In response to anti-CD3 plus anti-CD28 stimulation, Dicer-deleted T cells up-regulated CD69 faster and entered the first mitosis earlier than control T cells. In addition, activated Dicer(-/-) cells failed to rapidly down-regulate CD69 when removed from the TCR stimulus. As a probable consequence of this sustained CD69 expression, Dicer(-/-) T cells showed defective migration out of the central lymphoid organs in vivo. We identify miR-130/301, which are dramatically up-regulated following T-cell activation, as able to down-regulate CD69 expression via binding to a conserved site in the 3'UTR of CD69 mRNA. Thus, cellular functions dependent on Dicer expression are not required for the early steps in CD8(+) T-cell activation, but are essential for their survival and accumulation.
authors.affiliation: Department of Immunology and The Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
authors.forename: Nu
authors.initials: N
authors.lastname: Zhang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bevan
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology*; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D043244:Ribonuclease III / Q000235:genetics / Q000276:immunology*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D037181:Lectins, C-Type; D035683:MicroRNAs; D011948:Receptors, Antigen, T-Cell; D043244:Ribonuclease III; D000099192:CD69 Antigens