Mitochondrial metabolism is essential for invariant natural killer T cell development and function
In: Proceedings of the National Academy of Sciences, Jg. 118 (2021-03-22)
Online
unknown
Zugriff:
Significance We show CD1d-restricted natural killer (NK)T cells have distinct metabolic profiles compared with CD4+ conventional T cells. Mature NKT cells have poor fatty acid oxidation and exhibit reduced mitochondrial respiratory reserve in the steady state. In addition, NKT cell development is more sensitive to alterations in mitochondrial electron transport chain function than conventional T cells. Using T cell-specific mitochondrial complex III ablation in mice, we further demonstrate that mitochondrial metabolism plays a crucial role in NKT cell development and function by modulating T cell receptor/interleukin-15 signaling and NFAT activity. Collectively, our data provide evidence for a critical role of mitochondrial metabolism in NKT cell development and activation, opening a new avenue for NKT cell-based immunotherapy by manipulating NKT cell metabolism.
Conventional T cell fate and function are determined by coordination between cellular signaling and mitochondrial metabolism. Invariant natural killer T (iNKT) cells are an important subset of “innate-like” T cells that exist in a preactivated effector state, and their dependence on mitochondrial metabolism has not been previously defined genetically or in vivo. Here, we show that mature iNKT cells have reduced mitochondrial respiratory reserve and iNKT cell development was highly sensitive to perturbation of mitochondrial function. Mice with T cell-specific ablation of Rieske iron-sulfur protein (RISP; T-Uqcrfs1−/−), an essential subunit of mitochondrial complex III, had a dramatic reduction of iNKT cells in the thymus and periphery, but no significant perturbation on the development of conventional T cells. The impaired development observed in T-Uqcrfs1−/− mice stems from a cell-autonomous defect in iNKT cells, resulting in a differentiation block at the early stages of iNKT cell development. Residual iNKT cells in T-Uqcrfs1−/− mice displayed increased apoptosis but retained the ability to proliferate in vivo, suggesting that their bioenergetic and biosynthetic demands were not compromised. However, they exhibited reduced expression of activation markers, decreased T cell receptor (TCR) signaling and impaired responses to TCR and interleukin-15 stimulation. Furthermore, knocking down RISP in mature iNKT cells diminished their cytokine production, correlating with reduced NFATc2 activity. Collectively, our data provide evidence for a critical role of mitochondrial metabolism in iNKT cell development and activation outside of its traditional role in supporting cellular bioenergetic demands.
Titel: |
Mitochondrial metabolism is essential for invariant natural killer T cell development and function
|
---|---|
Autor/in / Beteiligte Person: | Sena, Laura A. ; Kumar, Amrendra ; Weng, Xiufang ; Cao, Liang ; Visvabharathy, Lavanya ; He, Ying ; Chyung Ru Wang ; Morgun, Eva ; Weinberg, Samuel E. ; Zhao, Jie ; Chandel, Navdeep S. |
Link: | |
Zeitschrift: | Proceedings of the National Academy of Sciences, Jg. 118 (2021-03-22) |
Veröffentlichung: | Proceedings of the National Academy of Sciences, 2021 |
Medientyp: | unknown |
ISSN: | 1091-6490 (print) ; 0027-8424 (print) |
DOI: | 10.1073/pnas.2021385118 |
Schlagwort: |
|
Sonstiges: |
|