Positive and negative selection of T cells in T-cell receptor transgenic mice expressing a bcl-2 transgene.
To explore the role of bcl-2 in T-cell development, a bcl-2 transgene was introduced into mice expressing a T-cell receptor (TCR) transgene encoding reactivity for the mouse male antigen HY presented by the H-2Db class I antigen of the major histocompatibility complex (MHC). Normal thymic development is contingent on the ability of immature thymocytes to interact with self-MHC molecules presented by thymic stroma (positive selection). Thus, thymocyte numbers are low in female anti-HY TCR transgenic mice with a nonselecting (H-2Dd) background. Expression of bcl-2 inhibited the death of nonselectable thymocytes since, strikingly, female H-2Dd bcl-2/TCR transgenic mice developed normal numbers of CD4+CD8+ thymocytes, although these did not mature further into functional T cells. Hence, TCR-MHC interaction may induce positive selection through two signals, one which saves cells from death by increasing Bcl-2 synthesis and another which promotes maturation. Male H-2Db anti-HY TCR transgenic mice normally have a very small thymus, due to deletion of the self-reactive T cells. Expression of bcl-2 reduced the efficiency of deletion, since bcl-2/TCR transgenic male mice accumulated 4- to 6-fold more thymocytes than did TCR transgenic male littermates. Anti-HY TCR-expressing cells were also more numerous in the peripheral lymphoid tissues, but these cells expressed abnormally low levels of CD8 co-receptor and were not responsive to the HY antigen. Thus, although bcl-2 expression hampers the deletion of immature self-reactive cells in the thymus, self-tolerance is maintained.
Strasser
A
A
Walter and Eliza Hall Institute of Medical Research, P.O. Royal Melbourne Hospital, Victoria, Australia.
Harris
A W
AW
von Boehmer
H
H
Cory
S
S
D000818:Animals; D015551:Autoimmunity; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D002454:Cell Differentiation; D002470:Cell Survival; D005260:Female; D006183:H-2 Antigens / Q000276:immunology; D006182:H-Y Antigen / Q000235:genetics; D064532:Histocompatibility Antigen H-2D; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D012641:Selection, Genetic; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D015704:CD4 Antigens; D016827:CD8 Antigens; D006183:H-2 Antigens; D006182:H-Y Antigen; D064532:Histocompatibility Antigen H-2D; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell