Regulation of nkt cell metabolism by plzf
Kumar A, Pyaram K, Yarosz E, Giri S, and Chang CH. Regulation of nkt cell metabolism by plzf. J Immunol 2018; 200(1 Suppl S):167.2.
Cellular metabolism and signaling pathways are the key regulators to determine T cell fate, survival and function, particularly during activation. Resting CD4 and CD8 T cells use oxidative phosphorylation as a primary energy source but switches to glycolysis upon activation, which is necessary to produce biomolecules for cell proliferation and function. Failure of this reprogramming is detrimental for T cell mediated immunity. However, little is understood about how NKT cells control their metabolism to survive and function. We found that NKT cells operate distinctly different metabolic programming from CD4 T cells for their survival and function. Supporting evidence includes that, unlike CD4 T cells, oxidative phosphorylation seems to be preferred over glycolysis in NKT cells even after stimulation as revealed by lower level of intracellular lactate produced by NKT cells than CD4 cells after activation. These cells also seem to have high energy as revealed by higher ATP in NKT cells. Although the proper maintenance and functions of stimulated NKT cells need glucose, they are sensitive to the elevated glycolytic potential compared to CD4 T cells resulting in spontaneous cell death accompanied by hyperproliferation. Importantly, PLZF is the essential regulator of NKT cells' metabolism so that similar changes of glucose metabolism were found in CD4 T cells expressing PLZF. Conversely, NKT cells with haplodeficient PLZF were more tolerant to increased glycolysis, strongly supporting the key role of PLZF in NKT cell metabolism and homeostasis. We are currently investigating the underlying mechanisms by which PLZF controls metabolism in NKT cells using several approaches including metabolomics.
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