Therapy with modified CD3-specific monoclonal antibodies has been shown to have both immediate and long-term benefits in some human autoimmune and allograft-transplantation settings. Now, a report in The Journal of Clinical Investigation indicates that one mechanism by which these antibodies might modulate the immune response is by inducing a population of CD8+CD25+ regulatory T cells.

The humanized CD3-specific monoclonal antibody hOKT3γ1(Ala-Ala) contains a modified Fc portion that reduces its ability to induce cytokine release (thereby reducing the adverse side-effects that are associated with its use). Previous studies have shown that those patients with new-onset type 1 diabetes who respond to treatment with hOKT3γ1(Ala-Ala) have a concomitant increase in the number of CD8+ T cells. Bisikirska et al. found that hOKT3γ1(Ala-Ala) induced human peripheral-blood mononuclear cells (PBMCs) to proliferate in vitro. More specifically, whereas the CD8+ T cells in the cultures divided multiple times, the CD4+ T cells divided only once or twice. Importantly, 3 months after treatment with hOKT3γ1(Ala-Ala), the ratio of CD4+ T cells to CD8+ T cells in the peripheral blood of patients correlated with the ratio of CD4+ T cells to CD8+ T cells following culture of their PBMCs with hOKT3γ1(Ala-Ala). This indicates that it might be possible to predict whether a patient will respond to treatment with hOKT3γ1(Ala-Ala) by analysing the in vitro response of their PBMCs to stimulation with the antibody.

Further analysis showed that CD4+ T cells proliferated in response to hOKT3γ1(Ala-Ala) if CD8+ T cells were removed from the PBMCs and that the response of CD4+ T cells to tetanus toxoid was inhibited in a dose-dependent manner by CD8+ T cells that had been pre-activated by hOKT3γ1(Ala-Ala). Inhibition was mediated by cell–cell contact and not by soluble factors such as interleukin-10 and transforming growth factor-β. When the hOKT3γ1(Ala-Ala)-stimulated CD8+ T-cell population was separated into CD25+ and CD25− populations, it was found that only the CD8+CD25+ T cells could inhibit the response of CD4+ T cells to superantigen. These CD8+CD25+ T cells were also shown to express increased levels of intracellular cytotoxic T-lymphocyte antigen 4 (CTLA4) and increased levels of mRNA encoding the transcription factor forkhead box P3 (FOXP3), which has been shown to be a marker of naturally occurring, CD4+CD25+ regulatory T cells in mice. A similar increase in FOXP3 mRNA was observed in CD8+CD25+ T cells isolated from patients with type 1 diabetes who had been treated with hOKT3γ1(Ala-Ala).

These data indicate that a population of cells with a phenotype similar to the CD8+CD25+ regulatory T cells that are induced in vitro by stimulation with hOKT3γ1(Ala-Ala) is induced in vivo following treatment with the antibody, leading the authors to suggest that these regulatory cells might be central to the beneficial effects that therapy with hOKT3γ1(Ala-Ala) has for patients with type 1 diabetes.