Treg sensitivity to FasL and relative IL-2 deprivation drive idiopathic aplastic anemia immune dysfunction
Authors listShok Ping Lim Benedetta Costantini Syed Mian Pilar Perez Abellan Shreyans A Gandhi Marc Martinez Llordella Juan Jose Lozano Rita Antunes Dos Reis Giovanni AM Povoleri Thanos P Mourikis Ander Abarrategi Linda Ariza-Mcnaughton Susanne Heck Jonathan M Irish Giovanna Lombardi Judith CW Marsh Dominique Bonnet Shahram Kordasti Ghulam J Mufti
Idiopathic aplastic anemia (AA) has two key characteristics: an autoimmune response against hematopoietic stem/progenitor cells and regulatory T cells (Tregs) deficiency. We have previously demonstrated reduction in a specific subpopulation of Treg in AA, which predict response to immunosuppression. The aims of the present study were to define mechanisms of Treg subpopulation imbalance and identify potential for therapeutic intervention. We have identified two mechanisms that lead to skewed Treg composition in AA. Firstly, FasL mediated apoptosis on ligand interaction and, secondly, relative IL-2 deprivation. We have shown that IL-2 augmentation can overcome these mechanisms. Interestingly, when high concentrations of IL-2 were used for in vitro Treg expansion cultures, AA Tregs were able to expand. The expanded populations expressed high level of p-BCL-2, which makes them resistant to apoptosis. Using a xenograft mouse model, the function and stability of expanded AA Tregs were tested. We have shown that these Tregs were able to suppress the macroscopic clinical features and tissue manifestations of T cell-mediated graft-versus-host disease. These Tregs maintained their suppressive properties as well as their phenotype in a highly inflammatory environment. Our findings provide an insight into the mechanisms of Treg reduction in AA. We have identified novel targets with potential for therapeutic interventions. Supplementation of ex vivo expansion cultures of Tregs with high concentrations of IL-2 or delivery of IL-2 directly to patients could improve clinical outcomes in addition to standard immunosuppressive therapy.