In vivo T-lymphocyte tolerance in the absence of thymic clonal deletion mediated by hematopoietic cells

Thymic negative selection renders the developing T-cell repertoire tolerant to self-major histocompatability complex (MHC)/peptide ligands, The major mechanism of induction of self-tolerance is thought to be thymic clonal del etion, ie, the induction of apoptotic cell death in thymocytes expressing a self-reactive T-cell receptor. Consistent with this hypothesis, in mice de ficient in thymic clonal deletion mediated by cells of hematopoietic origin , a twofold to threefold increased generation of mature thymocytes has been observed. Here we describe the analysis of the specificity of T lymphocyte s developing in the absence of clonal deletion mediated by hematopoietic ce lls. In vitro, targets expressing syngeneic MHC were readily lysed by activ ated CD8(+) T cells from deletion-deficient mice. However, proliferative re sponses of T cells from these mice on activation with syngeneic antigen pre senting cells were rather poor. In vivo, deletion-deficient T cells were in capable of induction of lethal graft-versus-host disease in syngeneic hosts . These data indicate that in the absence of thymic deletion mediated by he matopoietic cells functional T-cell tolerance can be induced by nonhematopo ietic cells in the thymus, Moreover, our results emphasize the redundancy i n thymic negative selection mechanisms. (C) 1999 by The American Society of Hematology.