The potential of human regulatory T cells generated ex vivo as a treatment for lupus and other chronic inflammatory diseases

Abstract

Regulatory T cells prevent autoimmunity by suppressing the reactivity of potentially aggressive self-reactive T cells. Contact-dependent CD4+ CD25+ 'professional' suppressor cells and other cytokine-producing CD4+ and CD8+ T-cell subsets mediate this protective function. Evidence will be reviewed that T cells primed with transforming growth factor (TGF)-beta expand rapidly following restimulation. Certain CD4+ T cells become contact-dependent suppressor cells and other CD4+ and CD8+ cells become cytokine-producing regulatory cells. This effect is dependent upon a sufficient amount of IL-2 in the microenvironment to overcome the suppressive effects of TGF-beta. The adoptive transfer of these suppressor cells generated ex vivo can protect mice from developing chronic graft-versus-host disease with a lupus-like syndrome and alter the course of established disease. These data suggest that autologous T cells primed and expanded with TGF-beta have the potential to be used as a therapy for patients with systemic lupus erythematosus and other chronic inflammatory diseases. This novel adoptive immunotherapy also has the potential to prevent the rejection of allogeneic transplants.

Figure 1

The role of transforming growth factor-β (TGF-β) in the differentiation pathway of CD8⁺ regulatory T cells. In response to antigen stimulation, the combination of IL-2 produced by CD4⁺ cells and the active form of TGF-β produced by natural killer (NK) cells or macrophages (not shown) induce CD8⁺ cells to lose their cytotoxic potential and become regulatory, TGF-β-producing, Th3-like cells. IL-2 also enhances the extracellular conversion of TGF-β from the latent to the biologically active form.

Figure 2

The role of transforming growth factor-β (TGF-β) in the differentiation pathway of CD4⁺ regulatory T cells. Following T-cell activation where a sufficient amount of IL-2 is produced to overcome the inhibitory effects of TGF-β, the costimulatory effects of this cytokine induce the precursors of CD4⁺ CD25⁺ T cells to become contact-dependent 'professional' suppressor cells or induces CD4⁺ CD25^- cells to produce immunosuppressive quantities of TGF-β . IFN, interferon; Tr-1, Treg 1 regulatory CD4⁺ cells.