Early degenerate selection of thymocytes by class I major histocompatibility complex.
Ontogeny of T cells is accomplished in the thymus by a process of positive selection, in which interaction of the T cell receptor (TcR) expressed on CD4+8+ thymocytes with self major histocompatibility complex (MHC), expressed on cortical epithelial cells, determines the progress along the maturation pathway and confers self restriction to T cells. Conversely, cells behaving as self reactive by interaction with bone marrow-derived antigen-presenting cells are negatively selected by apoptosis. We show here that the presence of a class I-restricted soluble TcR (sTcR) in the fetal thymic microenvironment, early in T cell ontogeny, determines an enhanced negative selection of a sizeable number of CD4+8+ thymocytes, which have been previously subjected to a positive-selection event. We hypothesize that the generation of the mature 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 restriction element. A shift in this affinity threshold, caused by sTcR, results in the generation of cells acting in a self-reactive manner, which are then deleted. In extended fetal thymus organ culture in the presence of sTcR, we have also observed the appearance of mature CD8+ T cells, which once adoptively transferred to syngeneic nude mice are expanded in the periphery, consistent with an enhanced avidity of these cells for self MHC.
Grassi
F
F
Départment d'Immunologie, Institut Pasteur, UA 359 CNRS, Paris, France.
Barbier
E
E
Cazenave
P A
PA
D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D016827:CD8 Antigens / Q000032:analysis; D002454:Cell Differentiation; D005260:Female; D006183:H-2 Antigens / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009924:Organ Culture Techniques; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism*; D012995:Solubility; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D013950:Thymus Gland / Q000196:embryology*
D016827:CD8 Antigens; D006183:H-2 Antigens; D011948:Receptors, Antigen, T-Cell