Dissociation of thymic positive and negative selection in transgenic mice expressing major histocompatibility complex class I molecules exclusively on thymic cortical epithelial cells

Thymic positive and negative selection of developing T lymphocytes confront s us with a paradox: How can a T-cell antigen receptor (TCR)-major histocom patibility complex (MHC)/peptide interaction in the former process lead to transduction of signals allowing for cell survival and in the latter induce programmed cell death or a hyporesponsive state known as anergy? One of th e hypotheses put forward states that the outcome of a TCR-MHC/peptide inter action depends on the cell type presenting the selecting ligand to the deve loping thymocyte. Here we describe the development and lack of self-toleran ce of CD8(+) T lymphocytes in transgenic mice expressing MHC class I molecu les in the thymus exclusively on cortical epithelial cells. Despite the abs ence of MHC class I expression on professional antigen-presenting cells, no rmal numbers of CD8(+) cells were observed in the periphery. Upon specific activation, transgenic CD8(+) T cells efficiently lysed syngeneic MHC class I+ targets in vitro and in vivo, indicating that thymic cortical epitheliu m (in contrast to medullary epithelium and antigen-presenting cells of hema topoietic origin) is incapable of tolerance induction. Thus, compartmentali zation of the antigen-presenting cells involved in thymic positive selectio n and tolerance induction can (at least in part) explain the positive/negat ive selection paradox. (Blood, 2001;97:1336-1342) (C) 2001 by The American Society of Hematology.