Impaired thymic expression of tissue-restricted antigens licenses the de novo generation of autoreactive CD4+ T cells during murine acute GVHD (original) (raw)

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 medullary thymic epithelial cells expressing the autoimmune regulator (Aire(+)mTEC(high)) are targets of donor T-cell alloimmunity during aGVHD. A decline in mTEC(high) 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 aGVHD is a direct consequence of impaired thymic ectopic OVA expression in mTEC(high) cells. Our data therefore indicate that a functional compromise of the medullary mTEC compartment may link alloimmunity to the development of autoimmunity...