Investigating the topography of adaptive immunity in the cardiovascular system: Basic mechanisms and therapeutic potential (renewal).

A growing body of evidence suggests that inflammatory processes within the heart are an important cause of cardiac disorders and determinants of disease progression and outcome. These inflammatory mechanisms may be either primary or secondary (perhaps maladaptive) to the initial cardiac injury. While the role of innate immunity in cardiac inflammation has been extensively studied and clinical targeting of these mechanisms is currently being pursued, the mechanisms of activation and progression of adaptive immunity remain poorly defined, resulting in a paucity of diagnostic, prognostic and therapeutic tools. By dissecting the basic mechanism of T-cell trafficking, we have recently discovered a subset of cardiotropic T-lymphocytes (cT-cells) in humans and mice and shown that these cells selectively target the heart in human myocarditis. We have further described alternative mechanisms by which the T-cell response can be modulated by pharmacologically targeting metabolic pathways underpinning T-cell migration. We propose to exploit these findings by a programme of studies aimed at defining the mechanism of activation and progression of cardiac-specific adaptive immunity and its therapeutic modulation by immunometabolic targeting.