Myocardial Infarction Primes Autoreactive T Cells through Activation of Dendritic Cells

Abstract

SummaryPeripheral 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.

Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses

“…However, the TCR-M cells isolated from the med-LNs of both infarcted and sham-operated mice displayed markers of cell activation ( Figure 2H). These findings suggest that MYHCA is constitutively presented to CD4 + T cells in the heart-draining LNs of healthy mice, even in the absence of cardiac damage, as previously reported (21,34). TCR-M cells were virtually absent from sham-operated hearts, but they exhibited a differentiated phenotype in infarcted hearts ( Figure 2I).…”

“…Neither CD4 + nor FOXP3 + cells were found in the control hearts. T cells reportedly influence cardiac injury, repair, and remodeling in various organisms, ranging from fishes to mammals (16,(18)(19)(20)(21)56). Nevertheless, the question of whether post-MI autoimmune responses exert salutary or detrimental effects has remained debated (54).…”

“…Nevertheless, the question of whether post-MI autoimmune responses exert salutary or detrimental effects has remained debated (54). Independent laboratories have recently reported that T cells may foster early cardiac healing by modulating macrophage polarization (18), fibroblast activity (20), and extracellular purinergic metabolism (21). However, chronic T cell activation in the myocardium has also been reported to fuel the development of adverse remodeling in models of ischemic and stress overload-induced HF (19,(25)(26)(27).…”

“…The participation of T cells in myocardial inflammation and repair has been observed in many organisms, ranging from fishes (14) to mammals (15)(16)(17)(18)(19), indicating that it is an evolutionarily conserved phenomenon. Previous studies from our group and others indicated that CD4 + T cells become primed and proliferate in the mediastinal lymph nodes (med-LNs) (heart-draining LNs) of infarcted mice and then infiltrate the myocardium (16,18,20,21). Independent groups have reported that the Tregs (defined as FOXP3 + ) activated after MI exert salutary effects by accelerating the resolution of inflammation and promoting appropriate extracellular matrix deposition in the myocardial scar (14,18,20,22,23).…”

Inflammatory cells and their non-coding RNAs as targets for treating myocardial infarction

“…Mature DCs act as master regulators of T-cell auto-reactivity in the heart. Quantities of Th1 and Th17 cells increase in the presence of conventional DC (cDC1) post-MI, while Treg cells accumulate in the presence of a different dendritic subtype (cDC2) in the steady state [186]. cFos is an important regulator of DC maturation, which in turn regulates the activation of T cells.…”