Identification and Functional Characterization of Human Cd4+Cd25+ T Cells with Regulatory Properties Isolated from Peripheral Blood

Abstract

A subpopulation of peripheral human CD4+CD25+ T cells that expresses CD45RO, histocompatibility leukocyte antigen DR, and intracellular cytotoxic T lymphocyte–associated antigen (CTLA) 4 does not expand after stimulation and markedly suppresses the expansion of conventional T cells in a contact-dependent manner. After activation, CD4+CD25+ T cells express CTLA-4 on the surface detectable for several weeks. These cells show a G1/G0 cell cycle arrest and no production of interleukin (IL)-2, IL-4, or interferon (IFN)-γ on either protein or mRNA levels. The anergic state of CD4+CD25+ T cells is not reversible by the addition of anti-CD28, anti–CTLA-4, anti–transforming growth factor β, or anti–IL-10 antibody. However, the refractory state of CD4+CD25+ T cells was partially reversible by the addition of IL-2 or IL-4. These data demonstrate that human blood contains a resident T cell population with potent regulatory properties.

Certified Professionals

“…This may be secondary to the purity of the CD25 + cells used in the assay and the specific assay (protein or mRNA). As has been reported with murine CD25 + T cells 4 6, human CD25 + T cells appear to be capable of producing low levels of IL-10 and perhaps TGF-β, although equivalent levels of TGF-β mRNA were also detectable in stimulated CD25 − T cells 16. Suppression in cocultures of CD25 + /CD25 − T cells could be abrogated to some extent by the addition of IL-2, IL-4, or IL-15, alone or in combination.…”

“…Human CD25 + cells respond to TCR stimulation combined with IL-2, IL-4, and IL-15 although, even under these conditions, their proliferative responses do not approach those of similarly stimulated CD25 − T cells. CD25 + T cells were capable of suppressing the responses of CD25 − cells to stimulation with anti-CD3 or alloantigen 14 15 16 presented by mDCs. Once activated, their suppressor function is nonspecific as was shown in studies of murine CD25 + T cells 7.…”

“…Three papers in this issue 14 15 16 and three papers 17 18 19 appearing elsewhere now describe the properties of human CD4 + CD25 + T cells. Given the obsession of most cellular immunologists with the concept of separating functionally distinct populations of cells based on their differential expression of membrane antigens, it is surprising that 6 yr elapsed between the identification of these cells in the mouse and the confirmation of their existence in man.…”

“…We have been unable to confirm these findings and have recently shown that induction of CD25 + -mediated suppressor function appears to be independent of costimulatory signals mediated by the interaction of either CD28 or CTLA-4 with their ligands, CD80/CD86 (unpublished observations). All of the human studies 14 15 16 17 18 19 fail to demonstrate reversal of suppression when anti–CTLA-4 or its F(ab′) fragment 19 is added. Nevertheless, the in vivo studies of both Takahashi et al 20 and Read et al 21 strongly implicate a role for CTLA-4 at some stage in the induction of CD25 + -mediated suppressor function during the pathogenesis of autoimmunity.…”

Depletion of CD25+ cells from human T-cell enriched fraction eliminates immunodominance during priming with dendritic cells genetically modified to express a secreted protein

“…43 Cells with similar phenotype and function have been found in healthy humans. [44][45][46][47] Of interest for cancer immunotherapy is the fact that depleting these cells results in the induction of antitumor immune responses, particularly after tumor-specific vaccination. 48,49 One hypothesis is that depleting these CD4 þ CD25 þ regulatory T cells in humans enhances a polyclonal T-cell response.…”