Researchers in Ireland and Germany say they have identified how specific immune cells can work together in fat to cause inflammation that leads to weight gain and obesity. Their study “Innate PD-L1 limits T cell–mediated adipose tissue inflammation and ameliorates diet-induced obesity”, which is published in Science Translational Medicine, pinpoints new avenues to exploit the regulation of that inflammation in fat tissue, thereby suggesting new ways to manage obesity.
“Obesity has become a major health problem in the industrialized world. Immune regulation plays an important role in adipose tissue homeostasis; however, the initial events that shift the balance from a noninflammatory homeostatic environment toward inflammation leading to obesity are poorly understood,” write the investigators.
“Here, we report a role for the costimulatory molecule programmed death-ligand 1 (PD-L1) in the limitation of diet-induced obesity. Functional ablation of PD-L1 on dendritic cells (DCs) using conditional knockout mice increased weight gain and metabolic syndrome during diet-induced obesity, whereas PD-L1 expression on type 2 innate lymphoid cells (ILC2s), T cells, and macrophages was dispensable for obesity control.
“Using in vitro cocultures, DCs interacted with T cells and ILC2s via the PD-L1:PD-1 axis to inhibit T helper type 1 proliferation and promote type 2 polarization, respectively. A role for PD-L1 in adipose tissue regulation was also shown in humans, with a positive correlation between PD-L1 expression in visceral fat of people with obesity and elevated body weight. “Thus, we define a mechanism of adipose tissue homeostasis controlled by the expression of PD-L1 by DCs, which may be a clinically relevant finding with regard to immune-related adverse events during immune checkpoint inhibitor therapy.”
In their research, the scientists identified how “checkpoint proteins” and immune cells alter inflammatory cells within the fat tissue to cause obesity. In people with obesity (Body Mass Index BMI> 30 kg/m²) these changes in checkpoint expression in the visceral fat was predictive of the person’s weight.
The researchers then showed that modifications in the so-called immune checkpoint proteins of mice on a Western “high fat” diet were linked to dramatic reductions in the development of obesity and diabetes.
“This new process of checkpoint regulation of cells in visceral fat of obese individuals advances our understanding of how the immune system controls diet-induced weight gain that can lead to conditions such as obesity and type 2 diabetes,” says Padraic Fallon, from Trinity College Dublin’s School of Medicine.
“Our discovery has broader impacts on addressing how obesity influences co-morbidity with other diseases, as shown in the COVID-19 pandemic, where obese individuals that are infected with SARS-CoV-2 are more likely to develop severe disease that requires intensive care and also have an increased risk of mortality.”
“In our study, we analyzed the function of immune checkpoints on specific cells, and it is fascinating to see that a small change on one of many cell populations in the fat has such an impact on the outcome of the disease. Only through our basic research efforts using pre-clinical models, were we able to gain access to patients’ samples and link our findings to human disease,” adds Christian Schwartz, PhD, a former EMBO Fellow in Trinity and now a Principal Investigator at the University Hospital Erlangen.
“It will be interesting to investigate now how we can manipulate this checkpoint on specific cell populations of interest to help people with obesity.”
