Regulation and Maintenance of Adipose Tissue T cells

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ABSTRACT Adipose tissue (AT) is an active metabolic organ that contains a network of immune cells whose crosstalk regulates adipose tissue homeostasis. In response to obesity, these immune cells can become activated, expand, and secrete adipokines and pro-inflammatory cytokines that modify local and systemic insulin sensitivity and contribute to the development of metabolic dysfunction and type 2 diabetes. Promotion and maintenance of adipose tissue inflammation in the obese state has been shown to involve the activation of adipose tissue T cells (ATT), which potentiate the activity of pro-inflammatory adipose tissue macrophages (ATMs) in mouse models of obesity. There is a fundamental gap in our understanding of the mechanisms by which ATTs are maintained, their diversity relative to other T cell subsets, and the signals to which ATTs respond during adipose tissue remodeling and expansion. Our preliminary data assessing early ATT kinetics demonstrated that ATTs proliferate in response to the rapid AT expansion induced by short-term high-fat diet (HFD) feeding. Timepoints assessed in these experiments precede the substantial infiltration of pro- inflammatory ATMs associated with the obese state, suggesting ATTs play vital roles in the initiation of AT inflammation observed in the obese state. This proposal seeks to test the hypothesis that ATT proliferation in response to short-term HFD feeding requires signals from antigen presenting cells (APCs). Further, the proposed research will interrogate the establishment of memory ATT and the determinant which drive the priming of their responses to AT changes in the obese state. Lastly, the PI’s prior research uncovered a unique population of TCRαβ CD3+ CD4- CD8- double negative (DN) ATTs and will test the hypothesis that DN ATTs possess an immunoregulatory phenotype and function in maintaining AT homeostasis and controlling effector ATTs during development of obesity. To test these hypotheses, the proposed project will pursue the following Aims during the K99 phase of this award: 1) To determine driver(s) of ATT proliferation during short-term HFD feeding and 2) to identify phenotype and function of DN ATTs in the lean and obese state. During this time, the PI will receive research training in nutrient metabolism in mice, bioinformatics and sequencing analysis, and translational research in obesity and diabetes. During the independent R00 phase, the PI will continue these Aims and seek to 3) determine establishment of resident memory ATTs and signals required for their induction and maintenance. Completion of this work will have significant impact on identification of the regulators of ATT functions in lean and obese states and elucidate novel targets to suppress obesity-associated AT inflammation mediated by ATT responses. Training in proposed techniques outlined in the K99 phase will ensure successful formation of the PI’s independent research program centering on obesity-associated inflammation and metabolic dysfunction, and how ATTs contribute to the initiation, orchestration, and maintenance of AT inflammation and subsequent insulin resistance.