title: Defects in the Bcl-2-regulated apoptotic pathway lead to preferential increase of CD25 low Foxp3+ anergic CD4+ T cells.
abstract: Defects in the Bcl-2-regulated apoptotic pathway inhibit the deletion of self-reactive T cells. What is unresolved, however, is the nature and fate of such self-reactive T cells escaping deletion. In this study, we report that mice with such defects contained increased numbers of CD25(low)Foxp3(+) cells in the thymus and peripheral lymph tissues. The increased CD25(low)Foxp3(+) population contained a large fraction of cells bearing self-reactive TCRs, evident from a prominent increase in self-superantigen-specific Foxp3(+)Vβ5(+)CD4(+) T cells in BALB/c Bim(-/-) mice compared with control animals. The survival rate of the expanded CD25(low)Foxp3(+) cells was similar to that of CD25(high)Foxp3(+) CD4 T cells in vitro and in vivo. IL-2R stimulation, but not TCR ligation, upregulated CD25 on CD25(low)Foxp3(+)CD4(+) T cells in vitro and in vivo. The expanded CD25(low)Foxp3(+)CD4(+) T cells from Bim(-/-) mice were anergic but also had weaker regulatory function than CD25(high)Foxp3(+) CD4(+) T cells from the same mice. Analysis of Bim(-/-) mice that also lacked Fas showed that the peripheral homeostasis of this expanded population was in part regulated by this death receptor. In conclusion, these results show that self-reactive T cell escapes from thymic deletion in mice defective in the Bcl-2-regulated apoptotic pathway upregulate Foxp3 and become unresponsive upon encountering self-Ag without necessarily gaining potent regulatory function. This clonal functional diversion may help to curtail autoaggressiveness of escaped self-reactive CD4(+) T cells and thereby safeguard immunological tolerance.
authors: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. zhan@wehi.edu.au
authors: Yifan
authors: Y
authors: Zhan
authors: Yuxia
authors: Y
authors: Zhang
authors: Daniel
authors: D
authors: Gray
authors: Emma M
authors: EM
authors: Carrington
authors: Philippe
authors: P
authors: Bouillet
authors: Hyun-Ja
authors: HJ
authors: Ko
authors: Lorraine
authors: L
authors: O'Reilly
authors: Ian P
authors: IP
authors: Wicks
authors: Andreas
authors: A
authors: Strasser
authors: Andrew M
authors: AM
authors: Lew
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D000072224:Bcl-2-Like Protein 11; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2