Innate PD-L1 limits T cell-mediated adipose tissue inflammation and ameliorates diet-induced 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 understo...

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Bibliographic Details
Published in:	Science translational medicine Vol. 14; no. 635; p. eabj6879
Main Authors:	Schwartz, Christian, Schmidt, Viviane, Deinzer, Andrea, Hawerkamp, Heike C, Hams, Emily, Bayerlein, Jasmin, Röger, Ole, Bailer, Moritz, Krautz, Christian, El Gendy, Amr, Elshafei, Moustafa, Heneghan, Helen M, Hogan, Andrew E, O'Shea, Donal, Fallon, Padraic G
Format:	Journal Article
Language:	English
Published:	United States 09-03-2022
Subjects:	Adipose Tissue - metabolism Animals B7-H1 Antigen - metabolism Diet Immunity, Innate Inflammation Lymphocytes - metabolism Mice Obesity - metabolism T-Lymphocytes
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Summary:	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. 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.
ISSN:	1946-6242
DOI:	10.1126/scitranslmed.abj6879