Modulating expression of a BTB-ZF transcription factor in adipose resident NKT cells alters function and disrupts metabolism regulation.

Abstract

Abstract Natural killer T cells (NKTs) are potent modulators of the immune system that can regulate the function of other cell types largely through their rapid and robust production of a wide variety of cytokines. One tissue that relies on the interactions of NKT cells with various cell types is white adipose tissue. Adipose resident NKT cells (arNKTs) maintain tissue homeostasis and metabolism through anti-inflammatory interactions such as modulating macrophage functions and enhancing the proliferation and function of FoxP3-expressing Tregs. However, arNKTs are phenotypically distinct from other populations of NKT cells in their transcription factor expression. We have found that genetically modulating the expression of a BTB-ZF transcription factor in NKT cells alters the frequency and function of arNKTs, thereby altering weight gain and metabolic function. Our data show that sustained expression of the BTB-ZF transcription factor in arNKT cells leads to lower arNKT frequency, altered function, and enhanced weight gain in a model of obesity (60% high fat diet). While deletion of the transcription factor during NKT cell development leads to lower arNKT frequency, altered arNKT phenotype, and impaired weight gain when fed 60% high fat diet. Collectively, our data show that dynamic changes in the expression of a BTB-zinc finger transcription factor during NKT cell development and tissue-homing are required for normal arNKT cell function, and preservation of adipose tissue metabolism. Our findings imply that NKT cell inability to temporally regulate the expression of a single transcription factor may drive adipose tissue dysregulation and metabolic disease. Supported by NIH/NIAID R21 AI159066-01