T cell dysregulation in pediatric obesity 2266671

Abstract Introduction The prevalence of obesity has increased worldwide over the last three decades, including severe obesity increasing amongst US children in recent years. Unfortunately, most children with obesity become adults with obesity, highlighting the complexities of significant weight loss. To date, the mechanisms by which obesity impacts immune function is not well understood. Here, we assessed the peripheral immune landscape of two distinct groups: 1) healthy children across ages and body mass indices (BMI) at baseline and 2) the impact of weight loss in adolescent patients before and 6-12 months following bariatric surgery. Methods We integrated spectral flow cytometry, in vitro T cell assays, and single-cell RNA-sequencing of PBMCs to evaluate the impact of obesity in otherwise healthy children and the impact of weight loss in adolescents with severe obesity. Results Children living with obesity have dysregulated non-naive CD8+ T cells (Tnn), including increased expression of activation markers (e.g., PD-1, CD69, CD95) and production of effector cytokines (IL-2, IFN-γ, TNF-α, which were significantly associated with BMI. Surgically induced weight loss had relatively minor impacts on immune phenotype and function. Transcriptionally, CD8+ T cells were enriched for cytokine signaling pathways in children with increased BMI, including amplified NF-kB signaling. Conclusion These data demonstrate a pattern of CD8+ T cell dysregulation in obesity that is only somewhat normalized by surgical weight loss. Funding Source Chan Zuckerberg Initiative; Burroughs Wellcome Fund Topic Categories Immune Mechanisms of Human Disease (HUM)