title: IL-15 acts as a potent inducer of CD4(+)CD25(hi) cells expressing FOXP3.
abstract: IL-15 is a member of the gamma chain-dependent cytokines and known to affect innate and CD8(+) adaptive immune responses. Despite a growing interest in the use of IL-15 as an immunotherapeutic agent, the broad spectrum of immunoregulatory functions exerted by IL-15 has not been fully elucidated. Here, we demonstrate that IL-15 increases expression of CD25 and forkhead box transcription factor P3 (FOXP3), a master transcriptional regulator of regulatory T cells, in human peripheral CD4(+)CD25(-) T cells in the absence of antigenic stimulation. Comparisons involving IL-2 and IL-7 revealed that the induction of CD25(hi) and FOXP3 expression was most prominent with IL-15 and IL-2. More modest effects were seen with IL-7. Despite levels of FOXP3 expression comparable to that of conventional regulatory T cells, cytokine-induced CD4(+)CD25(hi)FOXP3(+) cells exerted only weak suppressor activity. Thus, the current study has demonstrated that IL-15 acts as a potent inducer of CD4(+)CD25(hi)FOXP3(+) cells in the periphery, and suggests a potential role for IL-15 in blunting immune activation. This study has provided further insights into the pleiotropic nature of IL-15 beyond the regulation of CD8(+) T cells.
authors.affiliation: Laboratory of Molecular Retrovirology, Clinical Services Program, SAIC-Frederick Inc, NCI-Frederick, Frederick, MD 21702, USA. himamichi@nih.gov
authors.forename: Hiromi
authors.initials: H
authors.lastname: Imamichi
authors.forename: Irini
authors.initials: I
authors.lastname: Sereti
authors.forename: H Clifford
authors.initials: HC
authors.lastname: Lane
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015153:Blotting, Western; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D015851:Interleukin-7 / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D019409:Interleukin-15; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015851:Interleukin-7; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D015759:Ionomycin; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; D013755:Tetradecanoylphorbol Acetate