Treg activation during allograft tolerance induction requires mitochondrial-induced TGFβ1 in type 1 conventional dendritic cells

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Abstract

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. Using a murine model deficient in cDC1s, we report cDC1s are required for donor antigen and costimulation blockade (DST + CoB) tolerance induction and survival of cardiac allografts. cDC1 deficiency led to decreases in CD4+CD25+FoxP3+ T cells within both allograft and spleen tissue of transplant recipients and this was found to be antigen specific. Donor antigen stimulation induced TGF-β1 expression both in vivo cDC1 and in vitro Flt3L derived cDC1. Genetic deletion of Tgfβ1 in cDC1s prevented induction of antigen specific CD4+CD25+FoxP3+ T cells and was associated with cardiac allograft rejection. In parallel, 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 expression of cDC1 TGF-β1, decreased antigen specific T regulatory cell populations, and impaired allograft tolerance. Taken together, our findings newly implicate cDC1s in strategies to preserve solid organ allografts and also implicate mitochondrial metabolism of cDC1s as a molecular mechanism to enhance the generation of antigen-specific CD4+CD25+FoxP3+ T cells through TGF-β1.

Authors

Samantha L Schroth, Lei Zhang, Rebecca T.L. Jones, Kristofor Glinton, Nikita L. Mani, Hiroyasu Inui, Jesse T. Davidson, Samuel E. Weinberg, Navdeep Chandel, Maria-Luisa Alegre, Edward B. Thorp