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.
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 (gammac) 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 gammac 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.
Yates
John
J
Regulatory T Cell Laboratory, Department of Immunology, Division of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 ONN, UK.
Rovis
Flavia
F
Mitchell
Peter
P
Afzali
Behdad
B
Tsang
J  Y-S
J
Garin
Marina
M
Lechler
R I
RI
Lombardi
Giovanna
G
Garden
O A
OA
D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D018920:Coculture Techniques; D016572:Cyclosporine / Q000494:pharmacology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D019409:Interleukin-15 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis* / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D002867:Chromones; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006684:HLA-DR Antigens; D019409:Interleukin-15; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D015851:Interleukin-7; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011948:Receptors, Antigen, T-Cell; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C491405:TNFRSF18 protein, human; D015847:Interleukin-4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D016572:Cyclosporine; D051057:Proto-Oncogene Proteins c-akt