Regulatory T cells in human disease and their potential for therapeutic manipulation

Abstract

Regulatory T cells are proposed to play a central role in the maintenance of immunological tolerance in the periphery, and studies in many animal models demonstrate their capacity to inhibit inflammatory pathologies in vivo. At a recent meeting [Clinical Application of Regulatory T Cells, 7-8 April 2005, Horsham, UK, organized by the authors of this review, in collaboration with the British Society for Immunology and Novartis] evidence was discussed that certain human autoimmune, infectious and allergic diseases are associated with impaired regulatory T-cell function. In contrast, evidence from several human cancer studies and some infections indicates that regulatory T cells may impair the development of protective immunity. Importantly, certain therapies, both those that act non-specifically to reduce inflammation and antigen-specific immunotherapies, may induce or enhance regulatory T-cell function. The purpose of this review was to summarize current knowledge on regulatory T-cell function in human disease, and to assess critically how this can be tailored to suit the therapeutic manipulation of immunity.

Figure 1

The development of CD4⁺ regulatory T cells (Tregs). The thymus naturally produces FOXP3 ⁺ CD4⁺ CD25⁺ Tregs, possibly by high-affinity engagement of the T-cell receptor (TCR) with self-ligand presented by the thymic stroma. In the periphery, some of the naïve CD4⁺ CD25^– T cells may also differentiate into FOXP3 ⁺ CD4⁺ CD25⁺ Tregs. Several inducible Tregs have been identified, including T helper type 1 (Th1), Th2, Th3 and interleukin (IL)-10-producing Tregs. Th1 and Th2 cells are included here as signals that drive one of these lineages impair the development of the other (e.g. IL-12 and IL-4). Although IL-10 Tregs and Th3 cells are shown in this figure to originate following appropriate stimulation of naïve CD4⁺ T cells, the possibility that they derive from previously activated effector T cells exists. iDC, immature dendritic cell; MHC, major histocompatibility complex; TGF, transforming growth factor.