Myocardial Infarction Primes Autoreactive T Cells through Activation of Dendritic Cells
Peripheral tolerance is crucial for avoiding activation of self-reactive T cells to tissue-restricted antigens. Sterile tissue injury can break peripheral tolerance, but it is unclear how autoreactive T cells get activated in response to self. An example of a sterile injury is myocardial infarction (MI). We hypothesized that tissue necrosis is an activator of dendritic cells (DCs), which control tolerance to self-antigens. DC subsets of a murine healthy heart consisted of IRF8-dependent conventional (c)DC1, IRF4-dependent cDC2, and monocyte-derived DCs. In steady state, cardiac self-antigen α-myosin was presented in the heart-draining mediastinal lymph node (mLN) by cDC1s, driving the proliferation of antigen-specific CD4+ TCR-M T cells and their differentiation into regulatory cells (Tregs). Following MI, all DC subsets infiltrated the heart, whereas only cDCs migrated to the mLN. Here, cDC2s induced TCR-M proliferation and differentiation into interleukin-(IL)-17/interferon-(IFN)γ-producing effector cells. Thus, cardiac-specific autoreactive T cells get activated by mature DCs following myocardial infarction.
|Keywords||autoimmunity, cardiac myosin, dendritic cell, gene expression, heart, IRF4, IRF8, myocardial infarction, tissue necrosis, tolerance|
|Persistent URL||dx.doi.org/10.1016/j.celrep.2017.02.079, hdl.handle.net/1765/98770|
|Grant||This work was funded by the European Commission 7th Framework Programme; grant id h2020/660448 - Elucidating the role of liver resident Kupffer cells in the regulation of the immune responses to intestinal antigens (KCs and Gut Antigens)|
Van der Borght, K. (Katrien), Scott, C.L, Nindl, V. (Veronika), Bouché, A. (Ann), Martens, L, Sichien, D, … Lambrecht, B.N.M. (2017). Myocardial Infarction Primes Autoreactive T Cells through Activation of Dendritic Cells. Cell Reports, 18(12), 3005–3017. doi:10.1016/j.celrep.2017.02.079