Human CD4+CD25+ thymocytes and peripheral T cells have immune suppressive activityin vitro

Abstract

CD4+CD25+ T cells in mice and rats are capable of transferring protection against organ‐specific autoimmune disease and colitis and suppressing the proliferation of other T cells after polyclonal stimulation in vitro. Here we describe the existence in humans of CD4+CD25+ T cells with the same in vitro characteristics. CD4+CD8–CD25+ T cells are present in both the thymus and peripheral blood of humans (∼ 10 % of CD4+CD8– T cells), proliferate poorly in response to mitogenic stimulation and suppress the proliferation of CD4+CD25– cells in co‐culture. This suppression requires cell contact and can be overcome by the addition of exogenous IL‐2. CD4+CD25+ cells from thymus and blood were poor producers of IL‐2 and IFN‐γ, and suppressed the levels of these cytokines produced by CD4+CD25– cells. However, CD4+CD25+ PBL produced higher levels of IL‐4 and similar amounts of IL‐10 as CD4+CD25– cells. Regulatory CD4+CD25+ T cells have an activated phenotype in the thymus with expression of CTLA‐4 and CD122 (IL‐2Rβ). The fact that CD4+CD25+ regulatory T cells are present with a similar frequency in the thymus of humans, ratsand mice, suggests that the role of these cells in the maintenance of immunological tolerance is an evolutionarily conserved mechanism.

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

“…The murine counter- part of this T cell subset has an established role in the prevention of organ-specific autoimmune disease, including experimental allergic encephalomyelitis [5,26]. A similar subpopulation of CD4 + CD25 high T cells is present in human peripheral blood and lymphoid organs [6][7][8][9][10][11][12][13]. From a few recent studies, it appears that T reg numbers are reduced or their function is impaired in patients with various autoimmune disorders [17][18][19][20][21][22][23][24].…”

“…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].…”

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“…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. It is also notable that the frequency of CD4 + CD25 + Tr cells is equivalent in the thymus of humans, rats, and mice 17. Thus, there appears to be remarkable evolutionary conservation across species in terms of the phenotype of the cell population responsible for T cell suppression in vivo.…”

“…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.…”