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 ch aracterized a human CD4(+)CD25(+) T cell subset, which constitutes 7-10 % o f CD4(+) T cells in peripheral blood and tonsil. These cells are a CD45RO()CD45RB(low) highly differentiated primed T cell population that is anergic to stimulation. Depletion of this small subset from CD4(+) T cells signifi cantly 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 experime nts suggest that suppression is not mediated via IL-4, IL-10 or TGF-beta an d 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-beta. However, the aner gic/suppressive state of these cells is maintained after cytokine rescue. T hese human regulatory cells are therefore a naturally occurring, highly sup pressive, apoptosis-prone population which are at a late stage of different iation. Further studies into their role in normal and pathological situatio ns in humans are clearly essential.