Cardiac inflammation occurs in cardiovascular diseases, including myocardial infarction (MI) and myocarditis. After myocardial injury, cardiac auto-antigens are released and may trigger breakdown of heart-specific tolerance, leading to cardiac infiltration of CD4+ T cells that aggravate myocardial injury, as well as to production of cardiac auto-antibodies. We showed that insufficient cardiac lymphangiogenesis aggravates cardiac inflammation post-MI (Henri et al Circulation 2016). Conversely, we demonstrated that cardiac-infiltrating CD4+ T cells suppress cardiac lymphangiogenesis (Houssari et al ATVB 2020). However, whether cardiac lymphatics are involved in maintenance of cardiac tolerance remains to be determined.
In a mouse model of experimental autoimmune myocarditis (EAM), CD4+ T cells constitute the main T cell population in the acute phase, whereas T regulatory cells (Treg) predominate at the subacute phase. While Treg therapy promisingly reduced acute cardiac inflammation in EAM, the potential long-term impact of Tregs in limiting adaptive immune responses, including auto-antibody production, and on the cardiac remodelling leading to heart failure is currently unknown.
In this project, we aim to investigate how different T cell subsets and lymphatics interact to modulate cardiac tolerance during myocarditis. In particular, better understanding of the cellular and molecular regulation of cardiac immunity may lead to identification of factors that limit expansion of heart-reactive T cells or antibodies with the aim to reduce development of heart failure. The specific aims are to: 1) Determine the molecular cross-talk between cardiac lymphatics and T cell subsets during development of cardiac auto-reactive T cells and autoantibodies in EAM model; 2) Assess correlation between T cell subsets and cardiac lymphatic alterations in patients with auto-immune myocarditis; 3) Investigate long-term therapeutic effects of immune-modulatory treatment in EAM model.
Theoretical knowledge: the candidate should have strong knowledge in immunology and molecular biology as well as basic knowledge in integrated physiology, especially cardiac function and vascular cell biology.
Practical skills: the candidate should be familiar with cell culture, cell biology (immunohistochemistry, western-blot) and molecular biology (RNA extraction and RTqPCR) technics. Skills in cell sorting and immune cell culture are highly appreciated.