Defects in the Bcl-2-Regulated Apoptotic Pathway Lead to Preferential Increase of CD25(low)Foxp3(+) Anergic CD4(+) T Cells

Zhan, YF; Zhang, YX; Gray, D; Carrington, EM; Bouillet, P; Ko, HJ; O&#39;Reilly, L; Wicks, IP; Strasser, A; Lew, AM

Author(s): Zhan, YF; Zhang, YX; Gray, D; Carrington, EM; Bouillet, P; Ko, HJ; O'Reilly, L; Wicks, IP; Strasser, A; Lew, AM;
Details: Publication Year 2011-08-15,Volume 187,Issue #4,Page 1566-1577
Journal Title: JOURNAL OF IMMUNOLOGY
Publication Type: Journal Article
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(+)V beta 5(+)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 escapees 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. The Journal of Immunology, 2011, 187: 1566-1577.
Publisher: AMER ASSOC IMMUNOLOGISTS
Keywords: TRANSCRIPTION FACTOR FOXP3; FAMILY-MEMBER BIM; ALPHA-CHAIN GENE; BH3-ONLY PROTEIN; AUTOREACTIVE THYMOCYTES; REGULATORY ELEMENTS; NEGATIVE SELECTION; THYMIC SELECTION; BCL-2 TRANSGENE; IL-2 RECEPTOR
Publisher's Version: https://doi.org/10.4049/jimmunol.1100027
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2011-08-15 12:00:00