International Immunology Advance Access originally published online on June 1, 2007
International Immunology 2007 19(6):785-799; doi:10.1093/intimm/dxm047
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The maintenance of human CD4+CD25+ regulatory T cell function: IL-2, IL-4, IL-7 and IL-15 preserve optimal suppressive potency in vitro
1 Regulatory T Cell Laboratory, Department of Immunology, Division of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 ONN, UK
2 Immunoregulation Laboratory, Department of Nephrology and Transplantation, Fifth Floor, Thomas Guy House, Guy's Hospital Campus, King's College London School of Medicine at Guy's, King's College and St Thomas' Hospitals, London SE1 9RT, UK
3 Department of Veterinary Clinical Sciences, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire AL9 7TA, UK
Correspondence to: O. A. Garden; E-mail: ogarden{at}rvc.ac.uk or o.garden{at}imperial.ac.uk
CD4+CD25+ regulatory T cells (Tregs) have far-reaching immunotherapeutic applications, the realization of which will require a greater understanding of the factors influencing their function and phenotype during ex vivo manipulation. In murine models, IL-2 plays an important role in both the maintenance of a functional Treg population in vivo and the activation of suppression in vitro. We have found that IL-2 maintains optimal function of human CD4+CD25+ Tregs in vitro and increases expression of both forkhead box protein 3, human nomenclature (FOXP3) and the distinctive markers CD25, cytotoxic T lymphocyte antigen-4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor superfamily member number 18 (GITR). Although IL-2 reduced spontaneous apoptosis of Tregs, this property alone could not account for the optimal maintenance of the regulatory phenotype. The inhibition of phosphatidylinositol 3-kinase (PI3K) signaling by LY294002, a chemical inhibitor of PI3K, abolished the maintenance of maximal suppressive potency by IL-2, yet had no effect on the up-regulation of FOXP3, CD25, CTLA-4 and GITR. Other common gamma chain (
c) cytokines—IL-4, IL-7 and IL-15—had similar properties, although IL-4 showed a unique lack of effect on the expression of FOXP3 or Treg markers despite maintaining maximal regulatory function. Taken together, our data suggest a model in which the c cytokines IL-2, IL-4, IL-7 and IL-15 maintain the optimal regulatory function of human CD4+CD25+ T cells in a PI3K-dependent manner, offering new insight into the effective manipulation of Tregs ex vivo.
Keywords: common gamma chain, FOXP3, LY294002, phosphatidylinositol 3-kinase
Transmitting editor: A. Cooke
Received 13 July 2006, accepted 23 March 2007.
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