Human anergic/suppressive CD4+CD25+ T cells: a highly differentiated and apoptosis-prone population

Abstract

Anergic/suppressive CD4+CD25+ T cells exist in animal models but their presence has not yet been demonstrated in humans. We have identified and characterized a human CD4+CD25+ T cell subset, which constitutes 7–10 % of CD4+ T cells in peripheral blood and tonsil. These cells are a CD45RO+CD45RBlow highly differentiated primedT cell population that is anergic to stimulation. Depletion of this small subset from CD4+ T cells significantly 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 experiments suggest that suppression is not mediated via IL‐4, IL‐10 or TGF‐β and 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‐β. However, the anergic/suppressive state of these cells is maintained after cytokine rescue. These human regulatory cells are therefore a naturally occurring, highly suppressive, apoptosis‐prone population which are at a late stage of differentiation. Further studies into their role in normal and pathological situations in humans are clearly essential.

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

“…5). As previously reported, T reg died more quickly than T eff [12]. Furthermore, IL-2 rescued significantly more T reg than T eff from cell death, which reflects the well known dependency of highly purified CD4 + CD25 high cells on exogenous IL-2 in vitro [35,36].…”

“…Within the human CD4 + subset only cells coexpressing high levels of CD25 appear to have potent regulatory function [6,7]. CD4 + CD25 high regulatory T cells (T reg ) are anergic to antigenic stimulation and actively downregulate activation and expansion of conventional T lymphocytes in a cell-contact-dependent and cytokine-independent manner [5, [8][9][10][11][12][13]. Although the molecular interactions and signaling pathways that are critical for their generation and function are nut fully elucidated, T reg require forkhead transcription factor scurfin encoded by the Foxp3 gene, which appears to control their development and regulatory properties [14][15][16].…”

Certified Professionals

“…Human CD25 + T cells also have the phenotype of activated/memory T cells in that they are predominantly CD45RO + and a variable number also express MHC class II antigens. In one study 18, they were also shown to be CD45RO + and CD45RB low which is consistent with T cells which have been restimulated by antigen multiple times. The expression of CD122 (IL-2R β-chain) was easily detectable on human CD25 + T cells, while its expression on murine CD25 + cells is controversial.…”

“…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.…”