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Eating too much for fear of gaining weight? New study in Science sub-publication: PD-L1 improves diet-induced obesity

Obesity has become a major health problem in many populations and obesity is strongly associated with many other diseases.

Previous studies have shown that obesity-associated inflammation leads to co-morbidities and that immune regulation plays an important role in adipose tissue homeostasis. There is growing evidence that the immune system is severely dysregulated in obese patients and leads to a mild inflammatory state. Immune cells play an important role in the stabilization of the internal environment of adipose tissue, and dysregulation of the balance between pro- and anti-inflammatory cells promotes the progression of obesity. However, how does the non-inflammatory homeostatic environment transform into the inflammatory state that leads to obesity? The mechanisms that initiate this chain of processes are not known.

Programmed death-ligand 1 (PD-L1) is one of the key molecules regulating adaptive immunity, and PD-L1 has been shown to be a potent regulator of T-cell polarization. It has been found that macrophages, dendritic cells and type 2 innate lymphoid cells (ILC2) express PD-L1 and regulate PD-1 expressing T cells and ILC2. antibody-mediated PD-L1 inhibits the release of brakes from TH1 cells in antitumor and autoimmune responses. Therefore, we hypothesized that PD-L1 plays an important role in maintaining the stability of the adipose tissue internal environment and investigated the cell-specific function of PD-L1 during obesity using transgenic mice in a model of diet-induced obesity and in samples from obese patients.

Recently, the specialized academic journal Science Translational Medicine published a new study in obesity in which researchers from Germany and Ireland used conditional knockout mice to investigate the role of the co-stimulatory molecule PD-L1 in restricting diet-induced obesity.

The researchers found that PD-L1 on dendritic cells can control adaptive immune responses within adipose tissue, thereby limiting diet-induced obesity. In mice on a high-fat diet, dendritic cell PD-L1 deficiency promoted increased obesity as well as impaired adipose tissue T-cell polarization. However, anti-PD-L1 monoclonal antibody treatment reduced glucose tolerance in mice on a high-fat diet. PD-L1 expression in adipose tissue was also increased in obese patients, suggesting that PD-L1 on dendritic cells may also counteract adipose inflammation in humans.

Functional ablation of PD-L1 on dendritic cells during diet-induced obesity using conditional knockout mice increased body weight and produced metabolic syndrome, whereas PD-L1 expression on type 2 intrinsic lymphocytes, T cells and macrophages was not necessary for obesity control.

By co-culture in vitro, dendritic cells interacted with T cells and ILC2 via the PD-L1:PD-1 axis, inhibiting helper T cell type 1 proliferation and promoting type 2 polarization, respectively. The study also demonstrated a role for PD-L1 in the regulation of human adipose tissue, with PD-L1 expression in visceral fat of obese patients positively correlating with weight gain. Thus, the researchers defined a mechanism of adipose tissue endostasis controlled by dendritic cells expressing PD-L1, which may be a clinically relevant finding for immune-related adverse events during immune checkpoint inhibitor therapy.

In vitro, dendritic cells interacted with CD4+ T cells and ILC2 via PD-L1:PD-1 interactions.

In mouse models, PD-L1 expressed on dendritic cells plays an important role as a potent regulator of adipose tissue immunity: first, adipose tissue dendritic cells express large amounts of PD-L1 in mice and humans; second, deficiency of structural PD-L1 and dendritic cell-specific PD-L1 leads to increased body weight, impairs metabolic function, and shifts T cell polarization toward TH1 ; and finally, PD-L1 blockade in vitro affects TH2 polarization and ILC2 function. Combined with the results of checkpoint inhibition in vivo in the substudy, the researchers found their direct effect on T cell polarization and weight loss, and these data suggest that PD-L1 on dendritic cells maintains a homeostatic environment in adipose tissue and can counteract inflammation.

Taken together, the results of this new study build on previous findings, confirming that anti-PD-L1 monoclonal antibody treatment reduces glucose tolerance in mice on a high-fat diet and pointing to a potential role for PD-L1 on dendritic cells to combat adipose inflammation in humans.

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