MicroRNA-133b Regulation of Th-POK Expression and Dendritic Cell Signals Affect NKT17 Cell Differentiation in the Thymus.
NKT17 cells represent a functional subset of Vα14 invariant NKT (iNKT) cells with important effector functions in infections and autoimmune diseases. The mechanisms that drive NKT17 cell differentiation in the thymus are still largely unknown. The percentage of NKT17 cells has a high variability between murine strains due to differential thymic differentiation. For example, the NOD strain carries a high percentage and absolute numbers of NKT17 cells compared with other strains. In this study, we used the NOD mouse model to analyze what regulates NKT17 cell frequency in the thymus and peripheral lymphoid organs. In accordance with previous studies showing that the zinc finger transcription factor Th-POK is a key negative regulator of thymic NKT17 cell differentiation in the thymus, our data indicate that excessive NKT17 cell frequency in NOD mice correlates with defective Th-POK expression by thymic Vα14iNKT cells. Moreover, we found that Th-POK expression is under epigenetic regulation mediated by microRNA-133b whose expression is reduced in Vα14iNKT cells of NOD mice. We also demonstrated in a conditional knockout model of dendritic cell (DC) depletion (CD11cCreXDTA.B6 and CD11cCreRosa26DTA.NOD mice) that DCs play a crucial role in regulating Vα14iNKT cell maturation and their acquisition of an NKT17 cytokine secretion phenotype in the thymus. Overall, our data show that mechanisms regulating NKT17 cell differentiation are unique and completely different from those of Vα14iNKT cells. Specifically, we found that epigenetic regulation through microRNA-133b-regulated Th-POK expression and signals provided by DCs are fundamental for thymic NKT17 cell differentiation.
Experimental Diabetes Unit-Diabetes Research Institute, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy; and.
Caterina
C
Di Pietro
Experimental Diabetes Unit-Diabetes Research Institute, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy; and.
Lorena
0000-0002-7480-5720
L
De Giorgi
Experimental Diabetes Unit-Diabetes Research Institute, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy; and.
Ilaria
I
Cosorich
Experimental Diabetes Unit-Diabetes Research Institute, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy; and.
Chiara
0000-0002-6803-8377
C
Sorini
Experimental Immunology Unit, Division of Immunology, Transplantation, and Infectious Diseases, Institute for Research, Hospitalization, and Health Care, San Raffaele Scientific Institute, 20132 Milan, Italy.
Maya
M
Fedeli
Experimental Diabetes Unit-Diabetes Research Institute, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy; and falcone.marika@hsr.it.
Marika
0000-0001-6080-5351
M
Falcone
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D035683:MicroRNAs / Q000235:genetics*; D055611:Natural Killer T-Cells / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013950:Thymus Gland / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
D035683:MicroRNAs; D014157:Transcription Factors; C517732:Mirn133 microRNA, mouse; C497211:Zbtb7b protein, mouse