Akt2 Regulates the Differentiation and Function of NKT17 Cells via FoxO-1-ICOS Axis
LinLin Niu1,2,3, Xingtian Xuan1,2,3, Jinzhi Wang1,2,3
1Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China.
Abstract:
As a critical linker between mTORC1 and mTORC2, Akt is important for the cell metabolism. The role of Akt in the function and development of B and T cells is well characterized, however, the role of Akt for development and function of iNKT cells is unknown. iNKT cells bridge the adaptive and innate immunity, and in this study, we found that the differentiation of NKT17 cells and IL17 production of NKT17 cells were disrupted in Akt2 KO mice. ICOS has been demonstrated to be critical for the differentiation of NKT17 cells and we found that ICOS mRNA and protein expression was reduced in Akt2 KO iNKT cells. As a consequence, phosphorylation of FoxO-1 was downregulated in Akt2 KO thymocytes but the sequestration of FoxO-1 in the nucleus of Akt2 KO iNKT cells was increased. The negative feedback loop between ICOS and FoxO-1 has been demonstrated in CD4+T follicular helper cells. Therefore our study has revealed a new intracellular mechanism in which Akt2 regulates ICOS expression via FoxO-1 and this signaling axis regulates the differentiation and function of NKT17 cells. This study provides a new linker between cell metabolism and function of iNKT cells.
Insights
Akt2 deficiency impairs NKT17 cell differentiation and IL-17 production by reducing ICOS expression via FoxO-1 regulation. This reveals a link between cell metabolism and iNKT cell function.
Area of Science:
- Immunology
- Cell Biology
- Metabolism
Background:
- Akt kinases link mTOR signaling to cell metabolism and immune cell function.
- The role of Akt in B and T cell development is known, but its role in invariant natural killer T (iNKT) cells is unclear.
- iNKT cells are crucial for bridging innate and adaptive immunity.
Purpose of the Study:
- To investigate the role of Akt in the development and function of iNKT cells.
- To elucidate the molecular mechanisms by which Akt influences iNKT cell subsets, particularly NKT17 cells.
Main Methods:
- Utilized Akt2 knockout (KO) mice to study iNKT cell development and function.
- Analyzed NKT17 cell differentiation and Interleukin-17 (IL-17) production.
- Assessed the expression of ICOS (Inducible T-cell costimulator) and FoxO-1 (Forkhead box protein O1).
Main Results:
- Akt2 deficiency disrupted NKT17 cell differentiation and IL-17 production.
- Reduced ICOS mRNA and protein expression was observed in Akt2 KO iNKT cells.
- Downregulated FoxO-1 phosphorylation and increased nuclear sequestration of FoxO-1 in Akt2 KO thymocytes.
Conclusions:
- Akt2 regulates ICOS expression through FoxO-1, impacting NKT17 cell differentiation and function.
- This study identifies a novel signaling axis linking cell metabolism (via Akt) to iNKT cell immunity.
- The findings provide new insights into the intracellular mechanisms governing iNKT cell responses.
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