This proposal addresses an important gap in our knowledge and understanding of the role of dendritic cells and innate immunity in immuno-metabolic dysfunction. Increasing evidence indicates that obesity and obesity-induced type 2 diabetes (T2D) is, in large part an inflammatory disorder mediated by both innate and adaptive immunity. At the cellular level, it is well recognized that inflammatory macrophages, designated as M1, play an important role in the low-grade inflammation in adipose tissue during the course of obesity and related metabolic complications including T2D. T lymphocytes, (CD4+, CD8+ and Foxp3+ Treg) and B cells are also found in the adipose tissue and the level of infiltration is correlated with the severity of obesity and metabolic dysfunction. Dendritic cells are central to linking innate and adaptive immune responses, responding through receptors that signal through MyD88, amongst others, to stimulate adaptive immune responses. These cells play a key role upstream of the adaptive immune T and B cells as well as interact with macrophages in early phases of the immune response. However, not much is known about the role of dendritic cells (DCs) in the immunopathogenesis of obesity and its complication T2D and the role of MyD88, an important adaptor protein that controls innate immunity in these metabolic disorders. The current application is designed to address this issue in both animal models of obesity and related T2D as well as patients with these disorders. This will be achieved by using a unique mouse model system of both """"""""gain-of-function"""""""" and """"""""loss-of-function"""""""" of MyD88 in DCs and the studies in patients with obesity and/or T2D who undergo gastric bypass surgery. Our study will be achieved by a close collaboration between the principal investigator, the co-PI and the collaborator, who are experienced investigators with the unique capacity to bridge basic and clinical science as well as the fields of immunobiology and diabetes/metabolism.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Abraham, Kristin M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
Zip Code
Pearson, James A; Wong, F Susan; Wen, Li (2016) The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes. J Autoimmun 66:76-88
Hu, Youjia; Jin, Ping; Peng, Jian et al. (2016) Different immunological responses to early-life antibiotic exposure affecting autoimmune diabetes development in NOD mice. J Autoimmun 72:47-56
Yuksel, M; Xiao, X; Tai, N et al. (2016) The induction of autoimmune hepatitis in the human leucocyte antigen-DR4 non-obese diabetic mice autoimmune hepatitis mouse model. Clin Exp Immunol 186:164-176
Deng, Chao; Xiang, Yufei; Tan, Tingting et al. (2016) Altered Peripheral B-Lymphocyte Subsets in Type 1 Diabetes and Latent Autoimmune Diabetes in Adults. Diabetes Care 39:434-40
Tai, Ningwen; Peng, Jian; Liu, Fuqiang et al. (2016) Microbial antigen mimics activate diabetogenic CD8 T cells in NOD mice. J Exp Med 213:2129-46
Tai, Ningwen; Wong, F Susan; Wen, Li (2015) The role of gut microbiota in the development of type 1, type 2 diabetes mellitus and obesity. Rev Endocr Metab Disord 16:55-65
Yuksel, Muhammed; Wang, Yipeng; Tai, Ningwen et al. (2015) A novel ""humanized mouse"" model for autoimmune hepatitis and the association of gut microbiota with liver inflammation. Hepatology 62:1536-50
Hu, Youjia; Peng, Jian; Tai, Ningwen et al. (2015) Maternal Antibiotic Treatment Protects Offspring from Diabetes Development in Nonobese Diabetic Mice by Generation of Tolerogenic APCs. J Immunol 195:4176-84
Gülden, Elke; Wong, F Susan; Wen, Li (2015) The gut microbiota and Type 1 Diabetes. Clin Immunol 159:143-53
Hu, Changyun; Wong, F Susan; Wen, Li (2015) Type 1 diabetes and gut microbiota: Friend or foe? Pharmacol Res 98:9-15