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

Abstract

Abstract Most CD4+CD25hiFOXP3+ regulatory T cells (Tregs) from adult peripheral blood express high levels of CD45RO and CD95 and are prone to CD95L-mediated apoptosis in contrast to conventional T cells (Tconvs). However, a Treg 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 Tregs compared with most Tregs. In contrast to Tregs 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 Tregs are not sensitive toward CD95L similar to naive Tregs from adult individuals. After short stimulation with anti-CD3/CD28 monoclonal antibodies (mAbs), cord blood Tregs 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 Tregs that are frequently found on adult memory Tregs. 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 Tregs.