It has been known for years that rodents harbor a unique population of CD4+CD25+ “professional” regulatory/suppressor T cells that is crucial for the prevention of spontaneous autoimmune diseases. Here we demonstrate that CD4+CD25+CD45RO+ T cells (mean 6% of CD4+ T cells) are present in the blood of adult healthy volunteers. In contrast to previous reports, these CD4+CD25+ T cells do not constitute conventional memory cells but rather regulatory cells exhibiting properties identical to their rodent counterparts. Cytotoxic T lymphocyte–associated antigen (CTLA)-4 (CD152), for example, which is essential for the in vivo suppressive activity of CD4+CD25+ T cells, was constitutively expressed, and remained strongly upregulated after stimulation. The cells were nonproliferative to stimulation via their T cell receptor for antigen, but the anergic state was partially reversed by interleukin (IL)-2 and IL-15. Upon stimulation with allogeneic (but not syngeneic) mature dendritic cells or platebound anti-CD3 plus anti-CD28 the CD4+CD25+ T cells released IL-10, and in coculture experiments suppressed the activation and proliferation of CD4+ and CD8+ T cells. Suppression proved IL-10 independent, yet contact dependent as in the mouse. The identification of regulatory CD4+CD25+ T cells has important implications for the study of tolerance in man, notably in the context of autoimmunity, transplantation, and cancer.
Summary CD4+ CD25+ regulatory T cells are increasingly recognized as central players in the regulation of immune responses. In vitro studies have mostly employed allogeneic or polyclonal responses to monitor suppression. Little is known about the ability of CD4+ CD25+ regulatory T cells to suppress antigen‐specific immune responses in humans. It has been previously shown that CD4+ CD25+ regulatory T cells anergize CD4+ T cells and turn them into suppressor T cells. In the present study we demonstrate for the first time in humans that CD4+ CD25+ T cells are able to inhibit the proliferation and cytokine production of antigen specific CD4+ and CD8+ T cells. This suppression only occurs when CD4+ CD25+ T cells are preactivated. Furthermore, we could demonstrate that CD4+ T‐cell clones stop secreting interferon‐γ (IFN‐γ), start to produce interleukin‐10 and transforming growth factor‐β after coculture with preactivated CD4+ CD25+ T cells and become suppressive themselves. Surprisingly preactivated CD4+ CD25+ T cells affect CD8+ T cells differently, leading to reduced proliferation and reduced production of IFN‐γ. This effect is sustained and cannot be reverted by exogenous interleukin‐2. Yet CD8+ T cells, unlike CD4+ T cells do not start to produce immunoregulatory cytokines and do not become suppressive after coculture with CD4+ CD25+ T cells.
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