PHD2 Deletion in CD8⁺ T Cells Worsens TAC-Induced Cardiac Inflammation, Heart Failure, and Pulmonary Remodeling

Cardiac inflammation is a key driver of cardiac fibrosis and heart failure. Cytotoxic CD8⁺ T cells play important roles in modulating inflammatory responses, especially during infections and autoimmune diseases. HIFs (hypoxia-inducible factors) regulate CD8⁺ T cell function and cardiac remodeling. However, the role of HIF in CD8⁺ T cells during heart failure development remains unclear.

We generated CD8⁺ T cell-specific PHD2 (prolyl hydroxylase domain protein 2)-deficient mice (PHD2^CKO), in which HIF bioavailability is increased due to the loss of PHD2. PHD2^CKO and wild-type littermates were subjected to pressure overload via transverse aortic constriction. Cardiac function, inflammation, and CD8⁺ T cell responses were assessed. CD8⁺ T cell metabolism was analyzed using Seahorse assays to measure extracellular acidification rate and oxygen consumption rate. HIF1α and HIF2α protein levels were measured by Western blotting.

Under baseline conditions, PHD2 deletion in CD8⁺ T cells had no effect on heart function or effector molecule expression. Following transverse aortic constriction, PHD2^CKO mice showed exacerbated cardiopulmonary inflammation, fibrosis, and dysfunction. These effects were associated with enhanced CD8⁺ T cell activation and cytokine production. In vitro, PHD2-deficient CD8⁺ T cells exhibited increased glycolysis (extracellular acidification rate), reduced oxidative phosphorylation (oxygen consumption rate), and elevated HIF1α-but not HIF2α-levels. Pharmacological inhibition of HIF1α, but not HIF2α, reversed these metabolic and functional changes.

PHD2 deletion in CD8⁺ T cells aggravates cardiopulmonary remodeling after pressure overload by enhancing CD8⁺ T cell activation and cytokine release via a HIF1α-dependent mechanism.