Dicer-dependent microRNA pathway controls invariant NKT cell development.
Invariant NK T (iNKT) cells are a separate lineage of T lymphocytes with innate effector functions. They express an invariant TCR specific for lipids presented by CD1d and their development and effector differentiation rely on a unique gene expression program. We asked whether this program includes microRNAs, small noncoding RNAs that regulate gene expression posttranscriptionally and play a key role in the control of cellular differentiation programs. To this aim, we investigated iNKT cell development in mice in which Dicer, the RNase III enzyme that generates functional microRNAs, is deleted in cortical thymocytes. We find that Dicer deletion results in a substantial reduction of iNKT cells in thymus and their disappearance from the periphery, unlike mainstream T cells. Without Dicer, iNKT cells do not complete their innate effector differentiation and display a defective homeostasis due to increased cell death. Differentiation and homeostasis of iNKT cells require Dicer in a cell-autonomous fashion. Furthermore, we identify a miRNA profile specific for iNKT cells, which exhibits features of activated/effector T lymphocytes, consistent with the idea that iNKT cells undergo agonist thymic selection. Together, these results define a critical role of the Dicer-dependent miRNA pathway in the physiology of iNKT cells.
Fedeli
Maya
M
Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, H San Raffaele Scientific Institute, Milan, Italy.
Napolitano
Anna
A
Wong
Molly Pui Man
MP
Marcais
Antoine
A
de Lalla
Claudia
C
Colucci
Francesco
F
Merkenschlager
Matthias
M
Dellabona
Paolo
P
Casorati
Giulia
G
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004722:Endoribonucleases / Q000235:genetics*; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D006131:Growth Inhibitors / Q000235:genetics; D008231:Lymphopenia / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D055611:Natural Killer T-Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D043244:Ribonuclease III; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000201:enzymology / Q000276:immunology
D006131:Growth Inhibitors; D035683:MicroRNAs; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases