EARLY DEGENERATE SELECTION OF THYMOCYTES BY CLASS-I MAJOR HISTOCOMPATIBILITY COMPLEX

Ontogeny of T cells is accomplished in the thymus by a process of posi tive selection, in which interaction of the T cell receptor (TcR) expr essed on CD4(+)8(+) thymocytes with self major histocompatibility comp lex (MHC), expressed on cortical epithelial cells, determines the prog ress along the maturation pathway and confers self restriction to T ce lls. Conversely, cells behaving as self reactive by interaction with b one marrow-derived antigen-presenting cells are negatively selected by apoptosis. We show here that the presence of a class I-restricted sol uble TcR (sTcR) in the fetal thymic microenvironment, early in T cell ontogeny, determines an enhanced negative selection of a sizeable numb er of CD4(+)8(+) thymocytes, which have been previously subjected to a positive-selection event. We hypothesize that the generation of the m ature thymic T cell repertoire stems from an interaction of TcR, under a critical affinity threshold, with a self peptide-MHC complex which is common to a great number of TcR specificities using the same restri ction element. A shift in this affinity threshold, caused by sTcR, res ults in the generation of cells acting in a self-reactive manner, whic h are then deleted. In extended fetal thymus organ culture in the pres ence of sTcR, we have also observed the appearance of mature CD8(+) T cells,which once adoptively transferred to syngeneic nude mice are exp anded in the periphery, consistent with an enhanced avidity of these c ells for self MHC.