Over the last three decades, there has been a striking rise in obesity, together with parallel increases in insulin resistance, type-2 diabetes, cardiovascular disease and certain cancers. A critical link between obesity and its downstream comorbidities is chronic low-grade inflammation promoted by secretion of pro-inflammatory mediators by ?angry? adipocytes and macrophages in visceral adipose tissue (VAT). Anti-inflammatory cells and molecules capable of reining in these processes remain poorly understood. In 2009, we reported a population of Foxp3+CD4+ regulatory T cells (Tregs) that is highly enriched in epididymal VAT (eVAT), but not in lymphoid or other nonlymphoid organs, of lean mice as they age. These cells have a distinct gene- expression profile, T cell receptor (TCR) repertoire and profile of mediator dependencies. eVAT Tregs are strikingly and specifically reduced in several insulin-resistant mouse models of obesity, and loss- and gain-of- function experiments have confirmed that they regulate local and systemic inflammation and metabolism. An analogous Treg population is present in human omentum. eVAT Tregs serve as a paradigm for Treg populations specifically adapted to survive and function within particular tissue environments. Over the last funding cycle, we made substantial strides in illuminating the biology of VAT Tregs: dissecting transcriptome modulation with age and diet; discovering a two-step, two-site scenario of diversification from lymphoid-organ Tregs; uncovering modes of molecular diversification, including the construction of a tissue- Treg transcription-factor network; and demonstrating dependencies on TCR specificity, Foxp3 and IL-33. Building on these findings, the overall goal of this proposed project is to elucidate newly uncovered cellular and molecular elements controlling the generation, homeostasis or function of eVAT Tregs. We will undertake three Specific Aims, each designed to address a hypothesis that emerged from results obtained during the last funding cycle. 1) To examine the precursor potential of the splenic PPAR?lo Treg compartment. 2) To identify factors that elicit, promote or guide the splenic PPAR?lo precursors of eVAT PPAR?hi Tregs. 3) To determine whether and how the homeostasis and function of eVAT Tregs are influenced by a circadian clock. These studies should yield important new information on cellular and molecular pathways involved in regulating the devastating downstream consequences of obesity. Identification of novel therapeutic targets within these pathways is especially important given the disconcerting increases in these disorders and the unacceptable side-effects of certain drug options.
This project focuses on the cellular and molecular pathways controlling the homeostasis and function of a unique population of regulatory T cells (Tregs) that resides in visceral adipose tissue of lean, but not obese, mice and humans, and is capable of directly regulating both inflammation and insulin resistance and, thereby, type-2 diabetes, cardiovascular diseases and certain cancers. Obesity and its downstream comorbidities are major health challenges of the 21st century. Specifically enhancing the representation or activity of adipose- tissue Tregs offers a potential alternative to current front-line insulin-sensitizing drugs, whose side-effects have sometimes elicited concern.
|Li, Chaoran; DiSpirito, Joanna R; Zemmour, David et al. (2018) TCR Transgenic Mice Reveal Stepwise, Multi-site Acquisition of the Distinctive Fat-Treg Phenotype. Cell 174:285-299.e12|
|DiSpirito, Joanna R; Zemmour, David; Ramanan, Deepshika et al. (2018) Molecular diversification of regulatory T cells in nonlymphoid tissues. Sci Immunol 3:|
|Kuswanto, Wilson; Burzyn, Dalia; Panduro, Marisella et al. (2016) Poor Repair of Skeletal Muscle in Aging Mice Reflects a Defect in Local, Interleukin-33-Dependent Accumulation of Regulatory T Cells. Immunity 44:355-67|
|Panduro, Marisella; Benoist, Christophe; Mathis, Diane (2016) Tissue Tregs. Annu Rev Immunol 34:609-33|
|Mathis, Diane (2016) IL-33, Imprimatur of Adipocyte Thermogenesis. Cell 166:794-795|
|DiSpirito, Joanna R; Mathis, Diane (2015) Immunological contributions to adipose tissue homeostasis. Semin Immunol 27:315-21|
|Kolodin, Dmitriy; van Panhuys, Nicolas; Li, Chaoran et al. (2015) Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab 21:543-57|
|Cipolletta, Daniela; Cohen, Paul; Spiegelman, Bruce M et al. (2015) Appearance and disappearance of the mRNA signature characteristic of Treg cells in visceral adipose tissue: age, diet, and PPAR? effects. Proc Natl Acad Sci U S A 112:482-7|
|Cohen, Paul; Levy, Julia D; Zhang, Yingying et al. (2014) Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 156:304-16|
|Burzyn, Dalia; Kuswanto, Wilson; Kolodin, Dmitriy et al. (2013) A special population of regulatory T cells potentiates muscle repair. Cell 155:1282-95|
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