Human CD4low CD25high regulatory T cells indiscriminately kill autologous activated T cells

The interest of the scientific community in regulatory CD4(+) T cells has reached an enormously high level. Common agreement is that they inhibit not only the proliferation of CD4 and CD8 lymphocytes, but also the activities of natural killer cells and macrophages. However, very important issues concerning actual mechanism(s) and specificity of the action of regulatory T cells (Tregs) upon responder cells are still unsolved or vague. The best known marker for Tregs is the expression of transcription factor FoxP3, widely used for their enumeration. It is known that FoxP3 inhibits cytokine production so the most probable action of Tregs is direct. However, FoxP3 expression cannot be used for functional studies in humans. Therefore we identified human peripheral blood Tregs as a distinct, very well-defined population of peripheral blood T cells with reduced CD4 and high CD25 expression (CD4(low) CD25(high)), which fulfils the current phenotypic criteria identifying the Tregs by simultaneously expressing high amounts of FoxP3. We conclude that the definition of a CD4(low) CD25(high) phenotype is enough to unambiguously detect and study the regulatory function of these cells. On the functional level, the CD4(low) Tregs are able to non-specifically suppress the proliferation of autologous, previously polyclonally activated CD4(+) and CD4(-) lymphocytes and to kill them by direct contact, probably utilizing intracellular granzyme B and perforin.