Visceral adipose tissue (VAT) is a primary site for storage of excess energy but it also serves as an important endocrine organ that impacts systemic metabolism. Chronic, low-grade inflammation of VAT, and eventually systemically, is one of the major drivers of obesity-associated insulin resistance and metabolic abnormalities. A unique population of Tregs, with a distinct antigen-receptor repertoire and transcriptional profile driven by the transcription factor PPARg resides in VAT, keeps inflammation in check, and regulates organismal metabolism. To facilitate the study of VAT Tregs, we have recently developed two novel mouse lines: a vTreg53 T cell receptor (TCR) transgenic (tg) mouse line based on an expanded VAT-Treg clone, which hosted an exaggerated population of VAT Tregs and had an improved metabolic tenor, and a PPARg-Tdtomato reporter mouse for lineage-tracing of potential VAT-Treg precursors in lymphoid tissues. Combining these mouse models with low-input and single cell “-omics” approaches, we identified that TCR, Foxp3, and IL-33 are critical factors for VAT-Treg accumulation, and uncovered a novel two-step process for acquiring the definitive VAT-Treg phenotype (Li et al., Cell, 2018). We have recently expanded these observations to Tregs residing in other non-lymphoid tissues, such as skin and liver (Li et al., PNAS, 2021). Furthermore, we identified that IFNa produced by local plasmacytoid dendritic cells (pDCs) is a major driver for the reduction of VAT Tregs during obesity (Li# et al., Cell Metabolism, 2021). Moving forward, we will further address:
- What are the key factors that control VAT-Treg homeostasis at steady state and their response to obesity?
- What are the novel VAT resident immune subsets that impact systemic metabolism and how are they modulated during obesity?
- How does viral infection in adipose tissue affect the VAT resident immunocytes and systemic metabolism?
Another area that the lab will focus on is the skin. As a first layer of defense of the body, the skin hosts numerous immune cells that are in constant dialogue with the environment and commensal microbes. Skin is also a very complex system that contains diverse structures, including hair follicles and a dermal white adipose tissue (dWAT) important for many aspects of skin function. A unique population of skin Tregs has been characterized. These cells are generated in the thymus and subsequently traffic to the skin in the first weeks of life. They preferentially locate near hair follicles in the skin and express a set of genes that arm them with unique functions in suppressing local inflammation, supporting wound healing, and promoting hair regeneration. Our recent study identified a distinct subset of PPARg+ Tregs in the skin, which is critical to limit IL-17A-mediated psoriatic inflammation. Interestingly, obesity drives the loss of these PPARg+ skin Tregs, which contributes to the increased severity of psoriasis in obese individuals (Sivasami et al., Immunity, 2023). Moving forward, we will further address:
- What factors dictate the unique characteristics of skin Tregs?
- What are the environmental factors that shape the skin Treg phenotype?
- What is the TCR clonality, antigen specificity, and heterogenity of skin Tregs?
- What is the impact of obesity on skin immunocytes and how does that contribute to skin inflammation?
The ultimate goal of the laboratory’s research is to identify novel pathways and factors that are utilized by immunocytes in a tissue-specific manner and harness them for better design of precision targeting strategies.