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.

Additional Metadata
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
Journal Cell Reports
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)
Citation
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