Regulatory T cells generated ex vivo as an approach for the therapy of autoimmune disease

Semin Immunol. 2004 Apr;16(2):135-43. doi: 10.1016/j.smim.2003.12.009.


Regulatory T cells control the reactivity of potentially harmful, self-reactive T cells and prevent autoimmune diseases. Significant progress has been made in the identification, derivation, and mechanism of action of T regulatory cells, previously called suppressor T cells. Heterogeneous T regulatory subsets can be grouped into naturally occurring and those induced in the periphery. Here, we consider whether we can harness T regulatory cells to function as a therapeutic agent for patients with established autoimmune diseases. Since the principal function of thymus-derived, natural CD4+CD25+ cells is to prevent autoimmunity, this subset would be an obvious choice. Besides their contact-dependent, cytokine-independent mechanism of action, they can also induce other CD4+ cells to become suppressor cells. However, only few natural CD4+CD25+ cells circulate in human peripheral blood. Alternatively, one can use IL-2 and TGF-beta to generate large numbers of CD4+CD25+ regulatory T cells ex vivo from naive T cells. These cells have the phenotypic and functional properties similar to natural CD4+CD25+ cells, including the capacity to induce CD4+CD25- cells to develop suppressive activity. These natural-like CD4+CD25+ regulatory T cells are the product of separate effects of IL-2 and TGF-beta on both natural CD4+CD25+ and CD4+CD25- cells. The ability of natural-like CD4+CD25+ cells to induce other CD4+CD25- cells to develop suppressive activity is both contact-dependent and cytokine-dependent. Thus, the effects of IL-2 and TGF-beta on both natural CD4+CD25+ cells and CD4+CD25- cells may trigger a continuous loop which results in the renewal of antigen-specific CD4+ regulatory T cells. These studies suggest that the adoptive transfer of CD4+ T regulatory cells generated ex vivo with IL-2 and TGF-beta as a treatment for autoimmune diseases may have sustained, long-term beneficial effects.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Adoptive Transfer / adverse effects
  • Adoptive Transfer / methods*
  • Animals
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / therapy*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / transplantation
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / transplantation
  • Cell Communication / drug effects
  • Cell Communication / immunology
  • Cell Communication / physiology
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Cell Division / drug effects
  • Cell Division / immunology
  • Graft Rejection / therapy
  • Graft vs Host Disease / therapy
  • Humans
  • Interleukin-10 / immunology
  • Interleukin-10 / physiology
  • Interleukin-2 / pharmacology
  • Interleukin-2 / physiology
  • Mitogens / pharmacology
  • Models, Immunological
  • Receptors, Interleukin-2 / immunology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / transplantation*
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta / physiology


  • Interleukin-2
  • Mitogens
  • Receptors, Interleukin-2
  • Transforming Growth Factor beta
  • Interleukin-10