Reactive Oxygen Species Regulate the Inflammatory Function of NKT Cells through Promyelocytic Leukemia Zinc Finger
Yeung-Hyen Kim1, Ajay Kumar1, Cheong-Hee Chang1
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.
Abstract:
Reactive oxygen species (ROS) are byproducts of aerobic metabolism and contribute to both physiological and pathological conditions as second messengers. ROS are essential for activation of T cells, but how ROS influence NKT cells is unknown. In the present study, we investigated the role of ROS in NKT cell function. We found that NKT cells, but not CD4 or CD8 T cells, have dramatically high ROS in the spleen and liver of mice but not in the thymus or adipose tissues. Accordingly, ROS-high NKT cells exhibited increased susceptibility and apoptotic cell death with oxidative stress. High ROS in the peripheral NKT cells were primarily produced by NADPH oxidases and not mitochondria. We observed that sorted ROS-high NKT cells were enriched in NKT1 and NKT17 cells, whereas NKT2 cells were dominant in ROS-low cells. Furthermore, treatment of NKT cells with antioxidants led to reduced frequencies of IFN-γ- and IL-17-expressing cells, indicating that ROS play a role in regulating the inflammatory function of NKT cells. The transcription factor promyelocytic leukemia zinc finger (PLZF) seemed to control the ROS levels. NKT cells from adipose tissues that do not express PLZF and those from PLZF haplodeficient mice have low ROS. Conversely, ROS were highly elevated in CD4 T cells from mice ectopically expressing PLZF. Thus, our findings demonstrate that PLZF controls ROS levels, which in turn governs the inflammatory function of NKT cells.
Insights
Reactive oxygen species (ROS) are crucial for NKT cell function, influencing their inflammatory responses. The transcription factor PLZF controls ROS levels, thereby governing NKT cell activity and differentiation.
Area of Science:
- Immunology
- Cell Biology
- Metabolism
Background:
- Reactive oxygen species (ROS) are metabolic byproducts acting as signaling molecules in physiological and pathological processes.
- While ROS are vital for T cell activation, their specific role in NKT cells remains unexplored.
Purpose of the Study:
- To investigate the function and regulation of ROS in NKT cells.
- To determine the relationship between ROS levels, NKT cell subsets, and inflammatory potential.
Main Methods:
- Analysis of ROS levels in different NKT cell populations and tissues.
- Assessment of NKT cell apoptosis and function under oxidative stress.
- Investigation of ROS production sources (NADPH oxidases vs. mitochondria).
- Evaluation of the impact of antioxidants on NKT cell cytokine production.
- Examination of the role of the transcription factor PLZF in ROS regulation.
Main Results:
- NKT cells exhibit significantly higher ROS levels in spleen and liver compared to thymus and adipose tissues.
- High ROS levels in NKT cells correlate with increased susceptibility to oxidative stress and apoptosis.
- Peripheral NKT cell ROS are mainly produced by NADPH oxidases.
- ROS-high NKT cells are enriched in NKT1 and NKT17 subsets, while ROS-low cells are dominant in NKT2.
- Antioxidant treatment reduces IFN-γ and IL-17 production by NKT cells.
- The transcription factor PLZF controls ROS levels in NKT cells, with PLZF deficiency leading to lower ROS and ectopic PLZF expression in CD4 T cells increasing ROS.
Conclusions:
- ROS play a critical role in regulating the inflammatory function of NKT cells.
- PLZF is a key regulator of ROS production in NKT cells, influencing their subset distribution and cytokine output.
- These findings highlight a novel mechanism controlling NKT cell-mediated immunity and inflammation.
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