Purpose: While survival after heart transplantation has improved acutely, chronic rejection and morbidity from immunosuppressant medication remains a challenge for patients. We investigated the influence of conventional dendritic cell 1 cells (cDC1s), a population described to attenuate inflammation in multiple disease models, on cardiac transplantation survival and tolerance induction.
Methods: B6 and cDC1 knock out (KO) mice were subjected to tolerization regimen of donor splenocytes (DST) plus anti-CD40L costimulation blocking antibody (CoB) and heterotopic heart transplantation. Intrinsic cDC1 reprogramming during tolerance induction was evaluated by single cell RNA sequencing (scSEQ) of DC enriched splenic cells from B6 mice receiving DST CoB.
Results: We observed decreased survival and impaired contractile function of cardiac allografts in cDC1 KO mice alongside a decrease in allograft and splenic T regulatory (Treg) cells following transplantation. There was a significant upregulation of cDC1 TGFβ-1 following DST CoB, thus we sought to identify cell intrinsic signaling for this response. scSEQ of splenic cDC1s revealed upregulation of electron transport chain (ETC) and TCR signaling pathways, implicating a metabolic link between cDC1s and Treg polarization. Culture of bone marrow derived DCs from mice deficient in ETC complex III in cDC1s with donor antigen revealed decreased cDC1 CD86 and TGFβ-1 expression.
Conclusions: These data imply a role for cDC1s in cardiac allograft survival and suggest requirements for cDC1 mitochondrial metabolic activation of TGFβ1 for the induction of allograft protective Tregs. Continued interrogation of cDC1 metabolic polarization may provide alternative avenues for therapeutic targets to prolong allograft survival and minimize morbidity.
