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Updated: Aug 25, 2026
Generation of Induced Regulatory T Cells from Primary Human Naïve and Memory T Cells
Published on: April 16, 2012
Regulatory T cells generated ex vivo as an approach for the therapy of autoimmune disease
David A Horwitz1, Song Guo Zheng, J Dixon Gray
1The Division of Rheumatology and Immunology, Department of Medicine, Keck School of Medicine of the University of Southern California, 2011 Zonal Avenue, HMR 711, Los Angeles, CA 90033, USA. dhorwitz@usc.edu
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.
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.
