Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3856-3862
In Vivo T-Lymphocyte Tolerance in the Absence of Thymic Clonal Deletion
Mediated by Hematopoietic Cells
Joost P.M. van Meerwijk and
H. Robson MacDonald
From the Ludwig Institute for Cancer Research, Lausanne Branch,
University of Lausanne, Epalinges, Switzerland.
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 deletion, ie, the induction of apoptotic cell death
in thymocytes expressing a self-reactive T-cell receptor. Consistent
with this hypothesis, in mice deficient 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 lymphocytes developing in
the absence of clonal deletion mediated by hematopoietic cells. In
vitro, targets expressing syngeneic MHC were readily lysed by activated
CD8+ T cells from deletion-deficient mice. However,
proliferative responses of T cells from these mice on activation with
syngeneic antigen presenting cells were rather poor. In vivo,
deletion-deficient T cells were incapable of induction of lethal
graft-versus-host disease in syngeneic hosts. These data indicate that
in the absence of thymic deletion mediated by hematopoietic cells
functional T-cell tolerance can be induced by nonhematopoietic cells in
the thymus. Moreover, our results emphasize the redundancy in thymic negative selection mechanisms.
