The CD27/CD70 pathway negatively regulates visceral adipose tissue-resident Th2 cells and controls metabolic homeostasis

Adipose tissue homeostasis relies on the interplay between several regulatory lineages, such as type 2 innate lymphoid cells (ILC2s), T helper 2 (Th2) cells, regulatory T cells, eosinophils, and type 2 macrophages. Among them, ILC2s are numerically the dominant source of type 2 cytokines and are considered as major regulators of adiposity. Despite the overlap in immune effector molecules and sensitivity to alarmins (thymic stromal lymphopoietin and interleukin-33) between ILC2s and resident memory Th2 lymphocytes, the role of the adaptive axis of type 2 immunity remains unclear. We show that mice deficient in CD27, a member of the tumor necrosis factor receptor superfamily, are more resistant to obesity and associated disorders. A comparative analysis of the CD4 compartment of both strains revealed higher numbers of fat-resident memory Th2 cells in the adipose tissue of CD27 knockout mice, which correlated with decreased programmed cell death protein 1-induced apoptosis. Our data point to a non-redundant role for Th2 lymphocytes in obesogenic conditions. [Display omitted] •CD27 upregulates PD-1 expression on fat-resident Th2 cells in an intrinsic manner•PD-1 shifts the fate of Th2 toward activation-induced cell death•CD27 deletion results in increased adaptive type 2 immunity in the adipose tissue•The adaptive axis of type 2 immunity protects against obesity and associated disorders The function of Th2 is impaired during obesity. Here, Englebert et al. show that CD27-deficient mice are resistant to obesity and metabolic disorders. This protection correlates with increased Th2 numbers and cytokine production, which sustain visceral eosinophils and RELMα+ macrophages. The data point to a role of PD-1 in this process.