Myocardial Infarction Primes Autoreactive T Cells through Activation of Dendritic Cells

Summary

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.

Graphical Abstract

Highlights

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  IRF8 ⁺ cDC1, IRF4 ⁺ cDC2, moDCs, and macrophages are the APCs of the murine heart

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  Self-antigen presentation in the steady state drives Treg development via cDC1s

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  Myocardial infarction promotes infiltration, activation, and maturation of all DCs

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  Myocardial infarction promotes priming of Th1/Th17 autoreactive T cells via cDC2s

Abstract

Van der Borght et al. demonstrate that myocardial infarction induces the priming of autoreactive CD4 ⁺ T cells specific for cardiac self-antigen α-myosin in the heart-draining lymph node through the maturation and migration of conventional dendritic cells. Using ex vivo co-culture systems, cDC2s are shown to be superior in presenting α-myosin.