BioProject

Decades of work have elucidated cytokine signaling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic, and inflammatory diseases. More...

Decades of work have elucidated cytokine signaling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic, and inflammatory diseases. More recent evidence indicates that obesity and other shifts in systemic metabolism can also influence the function of cells in the immune system, although the mechanisms and possible effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis (AD), we show that lean and obese mice mount strikingly different immune responses. Obesity converts the classical AD-associated type 2 T helper cell (TH2)-predominant disease into a more severe disease with prominent TH17 inflammation. In addition to this immunopathologic difference, we observed strikingly divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but significantly exacerbated disease in obese mice. Single-cell RNA sequencing (scRNA-seq) coupled with genome-wide binding analysis revealed decreased activity in nuclear receptor PPARg (peroxisome proliferator-activated receptor gamma) activity in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARg in T cells identified a novel function for PPARg as required for focusing the in vivo TH response towards a TH2-predominant state and preventing aberrant non-TH2 inflammation. Treatment of obese mice with a small molecule PPARg agonist prevented development of TH17 pathology in AD and unlocked robust therapeutic responsiveness to targeted anti-TH2 biologics. These studies reveal the effects of obesity on immunological disease and demonstrate a precision medicine approach to target the immune dysregulation caused by obesity to restore efficacy of a biological immunotherapy. Overall design: Mice were challenged with MC903-AD on their ears, and lesional CD4+ T cells were isolated by FACS sorting on Day 10 of the challenge for single cell sequencing using the 10X platform. Less...