Corruption of dendritic cell antigen presentation during acute GVHD leads to regulatory T-cell failure and chronic GVHD

Lucie Leveque-El Mouttie, Motoko Koyama, Laetitia Le Texier, Kate A Markey, Melody Cheong, Rachel D Kuns, Katie E Lineburg, Bianca E Teal, Kylie A Alexander, Andrew D Clouston, Bruce R Blazar, Geoffrey R Hill, Kelli P A MacDonald

Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality following allogeneic bone marrow transplantation (BMT) and is characterized by tissue fibrosis manifesting as scleroderma and bronchiolitis obliterans. The development of acute GVHD (aGVHD) is a powerful clinical predictor of subsequent cGVHD, suggesting that aGVHD may invoke the immunological pathways responsible for cGVHD. In preclinical models in which sclerodermatous cGVHD develops after a preceding period of mild aGVHD, we show that antigen presentation within MHC class-II of donor dendritic cells (DCs) is markedly impaired early after BMT. This is associated with a failure of regulatory T-cell (Treg) homeostasis and cGVHD. Donor DC-restricted deletion of MHC class-II phenocopied this Treg deficiency and cGVHD. Moreover, specific depletion of donor Treg after BMT also induced cGVHD, while adoptive transfer of Tregs ameliorated it. These data demonstrate that the defect in Treg homeostasis seen in cGVHD is a causative lesion and is downstream of defective antigen presentation within MHC class-II that is induced by aGVHD.