Activation of T-regulatory cells during allograft tolerance-induction requires mitochondrial-induced TGFB1 in type 1 conventional dendritic cells

The role of type 1 conventional dendritic cells (cDC1) in tolerance-induction to solid organ allografts is unknown and important for strategies that seek to prolong allograft viability. Utilizing a murine model deficient in cDC1s, we report cDC1s to be required for donor antigen and costimulation blockade (DST + CoB) tolerance-induction and survival of cardiac allografts. Single-cell RNA sequencing and metabolic analysis revealed upregulation of cDC1 mitochondrial metabolic signatures after in vivo exposure to DST + CoB. Genetic inactivation of cDC1 mitochondrial metabolism reduced both expression of cDC1 TGF-β1 and induction of antigen specific CD4+CD25+FoxP3+ T cells. Splenic cells magnetically enriched for DCs and CD45+ cells from mice infused with allogenic BALB/c splenocytes and 500μg anti-CD40L (LACoB) antigen 48 hours prior and subjected to single cell RNA sequencing.