Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation Short title: Alloreactivity toward thymic epithelial cells

Acute graft-vs.-host disease (aGVHD) impairs thymus-dependent T-cell regeneration in recipients of allogeneic bone marrow transplantation (BMT) through yet to be defined mechanisms. Here, we demonstrate in mice that MHC-mismatched donor T-cells home into the thymus of unconditioned recipients. There, activated donor T-cells secrete IFN-γ which in turn stimulates the programmed cell death of thymic epithelial cells (TEC). As TECs themselves are competent and sufficient to prime naive allospecific T-cells and to elicit their effector function, the elimination of host-type professional APC does not prevent donor T-cell activation and TEC apoptosis, thus precluding normal thymopoiesis in transplant recipients. Hence, strategies that protect TECs may be necessary to improve immune reconstitution following allogeneic BMT. For personal use only. on October 3, 2017. by guest www.bloodjournal.org From