Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death

Most CD4(+)CD25(hi)FOXP3(+) regulatory T cells (T-regs) from adult peripheral blood express high levels of CD45RO and CD95 and are prone to CD95L-mediated apoptosis in contrast to conventional T cells (T-convs). However, a T-reg subpopulation remained consistently apoptosis resistant. Gene microarray and 6-color flow cytometry analysis including FOXP3 revealed an increase in naive T-cell markers on the CD95L-resistant T-regs compared with most T-regs. In contrast to T-regs found in adult humans, most CD4(+)CD25(+)FOXP3(+) T cells found in cord blood are naive and exhibit low CD95 expression. Furthermore, most of these newborn T-reg are not sensitive toward CD95L similar to naive T-regs from adult individuals. After short stimulation with anti-CD3/CD28 monoclonal antibodies (mAbs), cord blood T-regs strongly up-regulated CD95 and were sensitized toward CD95L. This functional change was paralleled by a rapid up-regulation of memory T-cell markers on cord blood T-regs that are frequently found on adult memory T-reg. In summary, we show a clear functional difference between naive and memory Tregs that could result in different survival rates of those 2 cell populations in vivo. This new observation could be crucial for the planning of therapeutic application of T-reg.