Tipping the Balance in Metabolic Regulation: Regulating Regulatory T Cells by Costimulation

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A growing epidemic of obesity is threatening the health of millions of people around the world. In recent years, the fields of immunology and metabolism are rapidly converging (1). Studies have established that obesity is associated with systemic low-grade chronic inflammation, which may play a causal role in obesity-associated insulin resistance, type 2 diabetes, and other complications (2,3). Notably, many immune cells infiltrate and populate in tissues, such as adipose tissue, during obesity and influence nutrient metabolism and tissue inflammation (1). Despite these advances, however, how inflammatory responses are maintained at a low level in obesity remains poorly understood. This is an important question because an overt immune response in obesity would compromise the immune system’s ability to preserve immune “tolerance” of self while maintaining the ability to fight off foreign pathogens. T lymphocytes, both CD4+ and CD8+ T cells, play an essential role in the initiation and regulation of adaptive immunity to foreign and native antigens. CD4+ T lymphocytes recognize polypeptides presented by class II major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs), such as macrophages and dendritic cells. Activated effector CD4+ T cells release cytokines that recruit other immune cells to the area, leading to inflammation. In addition to functionally distinct effector T-helper (Th) 1, Th2, and Th17 cells, CD4+ effector T cells can differentiate into immunosuppressive CD4+ CD25+ regulatory T (Treg) …