Lack of negative selection of CD4 T cells by bone marrow (BM)-derived cells causes fatal autoimmunity manifested as acute GVHD (141.16)

Abstract

Abstract While it is well established that BM-derived APCs play an essential role in the induction of self-tolerance, the biological consequence of losing this tolerogenic mechanism has yet to be determined. We generated BM chimeras by transplanting BM from MHC II-/- B6 mice into lethally irradiated Rag-/- or WT B6 mice. Lymphopoesis in the recipient mice initially appeared normal, but 5 wks post BMT, most mice became rapidly ill and died shortly afterwards. Histological examination revealed extensive epithelial apoptosis of the GI tract and skin on a pauci-inflammatory background. The liver showed marked vasculitis. The thymus underwent rapid atrophy and loss of developing thymocytes. The heart, lung, kidney, brain, salivary glands, pancreas, pancreatic islets and gonads were not affected. CD4 T cells in the thymus reacted vigorously against B6 DCs in vitro. Although thymic selection of CD8 T cells was unaltered, the CD8 T cells in the lymph nodes of the diseased animals were activated. Transfer of spleen cells from the diseased animals into Rag-/- mice resulted in similar tissue damage and accelerated death of recipients, but no disease if the Rag-/- mice were MHC II-/-. Further experiments involving MHC II-/- BM to MHC I-/- chimeras demonstrated that expression of MHC I by host tissue is also required for disease development. Our findings demonstrate that a consequence of lack of negative selection of CD4 T cells by BM-derived cells is fatal autoimmunity manifested distinctively as acute GVHD. The results also suggest that aGVHD can be induced solely by CD4 T cells generated in the recipients if the donor BM cells lack the MHC II type expressed by thymic epithelial cells of the recipients.