Adipose tissue type 2 immunity at perivascular niches

• Applicant: Dr. Julia Sbierski-Kind
• Subject Area: Immunology ; Endocrinology, Diabetology, Metabolism
• Term: from 2019 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 419333196

Obesity is associated with low-grade adipose tissue inflammation, promoting the progression of type 2 diabetes. Adipose tissue is a critical endocrine organ, composed of various cell types that include immune cells possessing immunoregulatory properties. However, the physiologic roles of tissue-resident immune cells in healthy adipose tissue are poorly understood. In the proposed project, we focus on adipose tissue type 2 immunity, including group 2 innate lymphoid cells (ILC2) and regulatory T (Treg) cells and their function and regulation in lean and obese conditions and post-infectious challenges. For this purpose, we will employ in vivo mouse models, 3D confocal imaging, flow immunophenotyping, genomics and pathologic challenges. Recently, it has been found that ILC2s localize to perivascular niches expressing IL-33. IL-33, a nuclear cytokine, has been identified as major activator of adipose tissue ILC2 and Treg, protecting against excessive inflammation and obesity-induced insulin resistance. Our first aim is to determine how mesenchymal cells and type-2 immune cells interact at perivascular adipose niches in the context of obesity and insulin resistance. We will test how deletion of IL-33 and IL-33 signalling in niche mesenchymal cells affects ILC2 localization and cytokine production in high-fat diet mice. Second, we will investigate the impact of high-fat diet feeding and caloric restriction on adipose tissue IL-33 signaling and ILC2 function. Third, we will focus on immune-cell interactions at the perivascular niche. Our second aim is to determine the impact of infections on adipose tissue immune composition. First, we will determine how ILC2s affect the mesenchymal niche and memory T cell populations in high-fat diet adult mice using infectious models. Second, we plan to investigate the role of ILC2 signals to regulate mesenchymal niche cell accumulation and IL-33 release. The experiments proposed here will reveal the direct and indirect roles of IL-33 signalling in regulating ILC2 and Treg cells in the context of adipose tissue homeostasis. Our insight in function and regulation of tissue resident lymphocytes might help to define novel pathways leading to therapeutic opportunities for the treatment of obesity and type 2 diabetes.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Ari Molofsky, Ph.D.