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Central tolerance plays a critical role in eliminating self-reactive T cells specific for peripheral antigens. Here we show that central tolerance of MHC class I-restricted T cells specific for classic myelin basic protein (MBP), a component of the myelin sheath, is mediated by both bone marrow (BM)-derived and nonBM-derived cells. Unexpectedly, BM-derived cells induce tolerance directly by using classic MBP that they synthesize, whereas nonBM-derived cells mediate tolerance by crosspresenting classic MBP acquired from an exogenous source. Thus, tolerance to tissue-specific antigens can involve multiple cell types and mechanisms in the thymus, which may account for the limited spectrum of autoimmune syndromes observed when expression of tissue-specific antigens is impaired only in thymic epithelial cells.

Crosspresentation by nonhematopoietic and direct presentation by hematopoietic cells induce central tolerance to myelin basic protein