Obesity induces premature thymic involution and restricts T cell repertoire diversity (36.47)

Abstract

Abstract Yun-Hee Youm, Hyunwon Yang, Bolormaa Vandanmagsar, Jennifer Rood, K. Ganesh Kumar, Andrew A. Butler and Vishwa Deep Dixit Obesity increases risk of infections and cancer, suggesting adverse effects on immune-surveillance. Here we report that obesity compromises the mechanisms regulating T cell generation via inducing premature thymic involution. Diet-induced obesity reduced the total number of thymocytes and significantly increased apoptosis in developing T cell populations. Obesity accelerated the age-related reduction of naïve T cells and decreased T cell receptor excision circle bearing peripheral T cells, an index of recently generated T cells from thymus. Defects in thymopoiesis in obese mice were due to a reduction in the lymphoid progenitor pool and deterioration in the thymic stromal microenvironment. Interestingly, obesity also increased the frequency of thymic fibroblasts and reduced the number of thymic epithelial cells (TECs). Furthermore, the TECs of DIO mice displayed reduced expression of IL-7 and auto immune regulator (Aire) mRNA. Obesity induced via melanocortin 4 receptor (Mc4r) deficiency also constricted the T cell receptor repertoire diversity, recapitulating the thymic defects observed with diet-induced obesity. In humans, progressive adiposity with or without type-2-diabetes also compromised thymic output. Collectively, these findings establish that obesity constricts T cell diversity by accelerating age-related thymic involution.