• Nir Grabie, Andrew H Lichtman, and Robert Padera.
• Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, NRB Room 752N, 77 Avenue Louis Pasteur, Boston, MA, USA.
• Cardiovasc. Res. 2019 Apr 15; 115 (5): 869-877.

AbstractT lymphocyte-mediated immune responses in the heart are potentially dangerous because they can interfere with the electromechanical function. Furthermore, the myocardium has limited regenerative capacity to repair damage caused by effector T cells. Myocardial T cell responses are normally suppressed by multiple mechanisms of central and peripheral tolerance. T cell inhibitory molecules, so called immune checkpoints, limit the activation and effector function of heart antigen-reactive T cells that escape deletion during development in the thymus. Programmed cell protein death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) are checkpoint molecules homologous to the costimulatory receptor CD28, and they work to block activating signals from the T cell antigen receptor and CD28. Nonetheless, PD-1 and CTLA-4 function in different ways and at different steps in a T cell response to antigen. Studies in mice have established that genetic deficiencies of checkpoint molecules, including PD-1, PD-L1, CTLA-4, and lymphocyte activation gene-3, result in enhanced risk of autoimmune T cell-mediated myocarditis and increased pathogenicity of heart antigen-specific effector T cells. The PD-1/PD-L1 pathway appears to be particularly important in cardiac protection from T cells. PD-L1 is markedly up-regulated on myocardial cells by interferon-gamma secreted by T cells and PD-1 or PD-L1 deficiency synergizes with other defects in immune regulation in promoting myocarditis. Consistent with these studies, myocarditis has emerged as a serious adverse reaction of cancer therapies that target checkpoint molecules to enhance anti-tumour T cell responses. Histopathology and immunohistochemical analyses of myocardial tissue from immune checkpoint blockade (ICB)-treated patients echoes findings in checkpoint-deficient mice. Many questions about myocarditis in the setting of cancer immunotherapy still need to be answered, including the nature of the target antigens, genetic risk factors, and variations in the disease with combined therapies. Addressing these questions will require further immunological analyses of blood and heart tissue from patients treated with ICB.Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.

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