T-cell immunity in myocardial inflammation: pathogenic role and therapeutic manipulation

Abstract

T-cell-mediated immunity has been linked not only to a variety of heart diseases, including classic inflammatory diseases such as myocarditis and post-myocardial infarction (Dressler's) syndrome, but also to conditions without an obvious inflammatory component such as idiopathic dilated cardiomyopathy and hypertensive cardiomyopathy. It has been recently proposed that in all these conditions, the heart becomes the focus of T-cell-mediated autoimmune inflammation following ischaemic or infectious injury. For example, in acute myocarditis, an inflammatory disease of heart muscle, T-cell responses are thought to arise as a consequence of a viral infection. In a number of patients, persistent T-cell-mediated responses in acute viral myocarditis can lead to autoimmunity and chronic cardiac inflammation resulting in dilated cardiomyopathy. In spite of the major progress made in understanding the mechanisms of pathogenic T-cell responses, effective and safe therapeutic targeting of the immune system in chronic inflammatory diseases of the heart has not yet been developed due to the lack of specific diagnostic and prognostic biomarkers at an early stage. This has also prevented the identification of targets for patient-tailored immunomodulatory therapies that are both disease- and organ-selective. In this review, we discuss current knowledge of the development and functional characteristics of pathogenic T-cell-mediated immune responses in the heart, and, in particular, in myocarditis, as well as recent advances in experimental models which have the potential to translate into heart-selective immunomodulation.

Linked articles: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.

Figure 1

Panel A: Hypertension: (1) Murine models have demonstrated renal production of IL‐6 following exposure to Ang II (AT II). (2) IL‐6 is associated with an enhanced CD4+ Th17 subtype response as well as diminishing the differentiation of T cells towards T_reg cells. (3) IL‐17, from Th17 cells, has been shown to contribute to endothelial dysfunction, hypertension as well as deleterious cardiac remodelling in mouse models. Panel B: Myocardial inflammation: (1) HGF has been shown to be present following myocardial inflammation in a mouse model. (2) This can then act on the HGF receptor, c‐Met, on naïve T cells in draining LNs. (3) The HGF–cMet interaction on naïve T cells during priming has then been shown to instruct T cell cardiotropism (4). Panel C: Transplant models: Following transplantation (1), antigen presenting cells (APC) can then activate naïve T cells (2) via both the MHC‐T cell receptor interaction as well as the co‐stimulatory actions of B7 on the APC with CD‐28 on the T cell surface. Naïve T cell activation (3) can then lead to effector T cells that may mediate transplant rejection (4). As described in the text, blockade of the CD‐28 receptor improved graft survival in animal models (5).