CD4+CD25(high) regulatory cells in human peripheral blood

Thymectomy in mice on neonatal day 3 leads to the development of multiorgan autoimmune disease due to loss of a CD(+)CD25(+) T cell regulatory populat ion in their peripheral lymphoid tissues. Here, we report the identificatio n of a CD4(+) population of regulatory T cells in the circulation of humans expressing high levels of CD25 that exhibit in vitro characteristics ident ical with those of the CD4(+)CD25(+) regulatory cells isolated in mice. Wit h TCR cross-linking, CD4(+)CD25(high) cells did not proliferate but instead totally inhibited proliferation and cytokine secretion by activated CD4(+) CD25(-) responder T cells in a contact-dependent manner. The CD4(+)CD25(hig h) regulatory T cells expressed high levels of CD45RO but not CD45RA, akin to the expression of CD45RB(low) on murine CD4(+)CD25(+) regulatory cells. Increasing the strength of signal by providing either costimulation with CD 28 cross-linking or the addition of IL-2 to a maximal anti-CD3 stimulus res ulted in a modest induction of proliferation and the loss of observable sup pression in cocultures of CD4(+)CD25(high) regulatory cells and CD4(+)CD25( -) responder cells. Whereas higher ratios of CD4(+)CD25(high) T cells are r equired to suppress proliferation if the PD-L1 receptor is blocked, regulat ory cell function is shown to persist in the absence of the PD-1/PD-L1 or C TLA-4/B7 pathway. Thus, regulatory CD4 T cells expressing high levels of th e IL-2 receptor are present in humans, providing the opportunity to determi ne whether alterations of these populations of T cells are involved in the induction of human autoimmune disorders.