Human anergic/suppressive CD4+CD25+ T cells: a highly differentiated and apoptosis-prone population

Anergic/suppressive CD4+CD25+ T cells exist in animal models but their presence has not yet been demonstrated in humans. We have identified and characterized a human CD4+CD25+ T cell subset, which constitutes 7–10 % of CD4+ T cells in peripheral blood and tonsil. These cells are a CD45RO+CD45RBlow highly differentiated primedT cell population that is anergic to stimulation. Depletion of this small subset from CD4+ T cells significantly enhances proliferation by threefold in the remaining CD4+CD25– T cells, while the addition of isolated CD4+CD25+ T cells to CD4+CD25– T cells significantly inhibits proliferative activity. Blocking experiments suggest that suppression is not mediated via IL-4, IL-10 or TGF-β and is cell-contact dependent. Isolated CD4+CD25+ T cells are susceptible to apoptosis that is associated with low Bcl-2 expression, but this death can be prevented by IL-2 or fibroblast-secreted IFN-β. However, the anergic/suppressive state of these cells is maintained after cytokine rescue. These human regulatory cells are therefore a naturally occurring, highly suppressive, apoptosis-prone population which are at a late stage of differentiation. Further studies into their role in normal and pathological situations in humans are clearly essential.