Abstract
NKT17 cells represent a functional subset of Va14 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 Va14iNKT cells. Moreover, we found that Th-POK expression is under epigenetic regulation mediated by microRNA-133b whose expression is reduced in Va14iNKT 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 Va14iNKT 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 Va14iNKT 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.
| Original language | English |
|---|---|
| Pages (from-to) | 3271-3280 |
| Number of pages | 10 |
| Journal | Journal of Immunology |
| Volume | 197 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Oct 15 2016 |
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ASJC Scopus subject areas
- Immunology
Cite this
MicroRNA-133b regulation of Th-POK expression and dendritic cell signals affect nkt17 cell differentiation in the thymus. / Di Pietro, Caterina; De Giorgi, Lorena; Cosorich, Ilaria; Sorini, Chiara; Fedeli, Maya; Falcone, Marika.
In: Journal of Immunology, Vol. 197, No. 8, 15.10.2016, p. 3271-3280.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - MicroRNA-133b regulation of Th-POK expression and dendritic cell signals affect nkt17 cell differentiation in the thymus
AU - Di Pietro, Caterina
AU - De Giorgi, Lorena
AU - Cosorich, Ilaria
AU - Sorini, Chiara
AU - Fedeli, Maya
AU - Falcone, Marika
PY - 2016/10/15
Y1 - 2016/10/15
N2 - NKT17 cells represent a functional subset of Va14 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 Va14iNKT cells. Moreover, we found that Th-POK expression is under epigenetic regulation mediated by microRNA-133b whose expression is reduced in Va14iNKT 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 Va14iNKT 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 Va14iNKT 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.
AB - NKT17 cells represent a functional subset of Va14 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 Va14iNKT cells. Moreover, we found that Th-POK expression is under epigenetic regulation mediated by microRNA-133b whose expression is reduced in Va14iNKT 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 Va14iNKT 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 Va14iNKT 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.
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U2 - 10.4049/jimmunol.1502238
DO - 10.4049/jimmunol.1502238
M3 - Article
VL - 197
SP - 3271
EP - 3280
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 8
ER -