title: Regulatory T cells generated ex vivo as an approach for the therapy of autoimmune disease.
abstract: 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.
authors.affiliation: The 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
authors.forename: David A
authors.initials: DA
authors.lastname: Horwitz
authors.forename: Song Guo
authors.initials: SG
authors.lastname: Zheng
authors.forename: J Dixon
authors.initials: JD
authors.lastname: Gray
authors.forename: Ju Hua
authors.initials: JH
authors.lastname: Wang
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ohtsuka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamagiwa
mesh_terms: D019264:Adoptive Transfer / Q000009:adverse effects / Q000379:methods*; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000637:transplantation; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D006084:Graft Rejection / Q000628:therapy; D006086:Graft vs Host Disease / Q000628:therapy; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology / Q000502:physiology; D007376:Interleukin-2 / Q000494:pharmacology / Q000502:physiology; D008934:Mitogens / Q000494:pharmacology; D018448:Models, Immunological; D015375:Receptors, Interleukin-2 / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology / Q000502:physiology
chemical_list: D007376:Interleukin-2; D008934:Mitogens; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D016753:Interleukin-10