Friday, May 9, 2025
5/9/2025
Regulatory iNKT Cells Suppress Inflammation and Drive Thermogenesis - iNKT cells are powerful cytokine producing cells that are activated by self or foreign lipid antigens presented by CD1d. The structure of the lipid antigens and the nature of the antigen presenting cells (APC) polarize iNKT cells and drive distinct effector cytokines. iNKT cells may make Th1-like (NKT1), Th2-like (NKT2) and Th17-like (NKT17) responses determined either by their thymic differentiation or by the peripheral signals they encounter. iNKT cells play important roles in many infections, and they have been extensively studied in this proinflammatory context. Here, we dissect the main non-host defense role of iNKT cells in adipose tissue to control inflammation and drive fat burning via a thermogenic program, and promote metabolic homeostasis. Recently, we found that what was considered a homogeneous population of adipose iNKT cells, is actually composed of distinct iNKT cells subsets that we predict mediate undesirable inflammation (NKT1 cells) or beneficial IL-10 driven anti-inflammatory roles for M2 macrophages (NKT10 cells). Remarkably, we identified a NKT17 population in adipose tissue that we propose will mediate the weight loss inducing, fat burning and fat browning thermogenic program. We also show evidence of strong and persistent TCR stimulation of adipose iNKT cells at steady state with upregulation of Nur77, downregulation of IL-7R and a high proliferation rate, all of which are distinct from iNKT cells in other tissues. We propose to identify the unique role of adipocytes as APC in activating the regulatory iNKT cell functions in fat, and to reveal the nature of the natural lipid antigen for iNKT cells made in adipose tissue that drives their endogenous activation. In Aim 1, we define the iNKT cell subsets in adipose tissue that we expect to be NKT1, NKT10 and NKT17 and use surface markers NK1.1 and CD4 to separately reveal their functions in improving or worsening inflammation and obesity. In Aim 2, we identify the major lipid antigen in adipose tissue that drives iNKT cells and determine how it polarizes iNKT cell cytokine production. In Aim 3, we advance understanding of iNKT cell therapeutics by testing endogenous and synthetic lipid antigens, selectively targeting them to adipose tissue and determining the relevance of adipocyte vs macrophage APC. These aims will advance understanding of adipose iNKT cells subsets, the role each plays and how they respond to therapeutic targeting with important implications for adipose tissue inflammation, obesity, and type II diabetes.
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