Autologous stem cell transplantation benefits autoimmune patients through functional renewal and TCR diversification of the regulatory T cell compartment

Autologous hematopoietic stem cell transplantation (HSCT) is increasingly considered for patients with severe autoimmune diseases whose prognosis is poor with standard treatments. Regulatory T cells (Treg) are thought to be important for disease remission after HSCT. Eliciting the role of donor and host Treg in autologous HSCT is however not possible in humans due to autologous nature of the intervention. Therefore, we investigated their role during immune reconstitution and re-establishment of immune tolerance and their therapeutic potential following congenic bone marrow transplantation (BMT) in a proteoglycan-induced arthritis (PGIA) mouse model. In addition, we determined Treg T cell receptor CDR3 diversity before and after HSCT in patients with juvenile idiopathic arthritis and juvenile dermatomyositis. In the PGIA BMT model, after an initial predominance of host Treg, graft-derived Treg started dominating and displayed a more stable phenotype with better suppressive capacity. Patient samples revealed a striking lack of diversity of the Treg repertoire before HSCT. This ameliorated after HSCT confirming reset of the Treg compartment following HSCT. In the mouse model a therapeutic approach was initiated by infusing extra Foxp3(GFP+)Treg during BMT. Infusion of Foxp3(GFP+)Treg did not elicit additional clinical improvement but conversely delayed reconstitution of the graft-derived T cell compartment. These data indicate that HSCT-mediated amelioration of autoimmune disease involves renewal of the Treg pool. In addition, infusion of extra Treg during BMT results in a delayed reconstitution of T-cell compartments. Treg therapy may therefore hamper development of long-term tolerance and should therefore be approached with caution in the clinical autologous setting.