期刊
INTERNATIONAL IMMUNOLOGY
卷 19, 期 6, 页码 785-799出版社
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxm047
关键词
common gamma chain; FOXP3; LY294002; phosphatidylinositol 3-kinase
类别
资金
- Medical Research Council [G0500429] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
- MRC [G0500429] Funding Source: UKRI
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 upregulation of FOXP3, CD25, CTLA-4 and GITR. Other common gamma chain (gamma(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 they, 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.
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