Impaired T cell IRE1α-XBP1 signaling directs inflammation in experimental Heart Failure with Preserved Ejection Fraction

Heart Failure with Preserved Ejection Fraction (HFpEF) is a widespread syndrome with limited therapeutic options and poorly understood immune-pathophysiology. Using a two-hit preclinical model of cardiometabolic HFpEF that induces obesity and hypertension, we found that cardiac T cell infiltration and lymphoid expansion occur concomitantly with cardiac pathology, and that diastolic dysfunction, cardiomyocyte hypertrophy and cardiac phospholamban phosphorylation are T cell-dependent. Heart-infiltrating T cells were not restricted to cardiac antigens and were uniquely characterized by impaired activation of the Inositol-requiring enzyme-1α (IRE1α)-X-box binding protein 1 (XBP1) arm of the unfolded protein response. Notably, selective ablation of XBP1 in T cells enhanced their persistence in the heart and lymphoid organs of mice with preclinical HFpEF. Furthermore, T cell IRE1α-XBP1 activation was restored after withdrawal of the two comorbidities inducing HFpEF, resulting in partial improvement of cardiac pathology. Our results demonstrate that diastolic dysfunction and cardiomyocyte hypertrophy in preclinical HFpEF are T cell-dependent, and that reversible dysregulation of the T cell IRE1α-XBP1 axis is a T cell signature of HFpEF