Exogenous dendritic cell-derived exosomes promote Treg differentiation via IDO1-Kyn-AhR axis and improve cardiac function after myocardial infarction

Regulatory T cells (Tregs) play a vital role in cardiac remodeling after myocardial infarction (MI). Our previous study demonstrated that dendritic cell-derived exosomes (DEXs) improve cardiac function after MI by promoting Treg differentiation. However, the underlying mechanisms remain incompletely understood. In this study, we found that necrotic HL-1 cardiomyocyte supernatant-conditioned DEXs (MI-DEXs) expressed high level of indoleamine 2,3-dioxygenase 1 (IDO1), which led to increased kynurenine (Kyn) production and subsequently upregulation of aryl hydrocarbon receptor (AhR) in CD4 + T cells. Overexpression of IDO1 in MI-DEXs enhanced Treg differentiation and further improved cardiac function after MI, whereas knockdown of IDO1 attenuated these effects. In addition, pharmacological inhibition of AhR abolished the enhanced Treg differentiation and functional benefits induced by IDO1-overexpressing MI-DEXs, both in vitro and in vivo. Collectively, our findings reveal a novel mechanism by which MI-DEXs promote Treg differentiation via the IDO1-Kyn-AhR axis, and suggest that administration of MI-DEXs could be a potential intervention to facilitate cardiac repair after MI. • Dendritic cells promote the differentiation of CD4 + T cells into Tregs via exosomes. • MI-DEXs drive Treg differentiation via IDO1-Kyn-AhR axis. • IDO1 overexpression augments Treg expansion and cardiac repair post-MI. • AhR inhibition abolishes MI-DEX OE-IDO1 benefits in vitro and in vivo. • IDO1-Kyn-AhR axis is essential for MI-DEX-mediated cardioprotection.