Defects in the Bcl-2–Regulated Apoptotic Pathway Lead to Preferential Increase of CD25lowFoxp3+ 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 CD25lowFoxp3+ cells in the thymus and peripheral lymph tissues. The increased CD25lowFoxp3+ 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 CD25lowFoxp3+ cells was similar to that of CD25highFoxp3+ CD4 T cells in vitro and in vivo. IL-2R stimulation, but not TCR ligation, upregulated CD25 on CD25lowFoxp3+CD4+ T cells in vitro and in vivo. The expanded CD25lowFoxp3+CD4+ T cells from Bim−/− mice were anergic but also had weaker regulatory function than CD25highFoxp3+ 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.