Impaired thymic expression of tissue-restricted antigens licenses the de novo generation of autoreactive CD4+ T cells in acute GVHD.

During acute graft-versus-host disease (aGVHD) in mice, autoreactive T cells can be generated de novo in the host thymus implying an impairment in self-tolerance induction. As a possible mechanism, we have previously reported that mature medullary thymic epithelial cells (mTEChigh) expressing the autoimmune regulator are targets of donor T-cell alloimmunity during aGVHD. A decline in mTEChigh cell pool size, which purges individual tissue-restricted peripheral self-antigens (TRA) from the total thymic ectopic TRA repertoire, weakens the platform for central tolerance induction. Here we provide evidence in a transgenic mouse system using ovalbumin (OVA) as a model surrogate TRA that the de novo production of OVA-specific CD4+ T cells during acute GVHD is a direct consequence of impaired thymic ectopic OVA expression in mTEChigh cells. Our data, therefore, indicate that a functional compromise of the medullary mTEChigh compartment may link alloimmunity to the development of autoimmunity during chronic GVHD.