title: Gamma c-signaling cytokines induce a regulatory T cell phenotype in malignant CD4+ T lymphocytes.
abstract: In this study, we demonstrate that malignant mature CD4(+) T lymphocytes derived from cutaneous T cell lymphomas (CTCL) variably display some aspects of the T regulatory phenotype. Whereas seven cell lines representing a spectrum of primary cutaneous T cell lymphoproliferative disorders expressed CD25 and TGF-beta, the expression of FOXP3 and, to a lesser degree, IL-10 was restricted to two CTCL cell lines that are dependent on exogenous IL-2. IL-2, IL-15, and IL-21, all of which signals through receptors containing the common gamma chain, induced expression of IL-10 in the IL-2-dependent cell lines as well as primary leukemic CTCL cells. However, only IL-2 and IL-15, but not IL-21, induced expression of FOXP3. The IL-2-triggered induction of IL-10 and FOXP3 expression occurred by signaling through STAT3 and STAT5, respectively. Immunohistochemical analysis of the CTCL tissues revealed that FOXP3-expressing cells were common among the CD7-negative enlarged atypical and small lymphocytes at the early skin patch and plaque stages. Their frequency was profoundly diminished at the tumor stage and in the CTCL lymph node lesions with or without large cell transformation. These results indicate that the T regulatory cell features are induced in CTCL T cells by common gamma chain signaling cytokines such as IL-2 and do not represent a fully predetermined, constitutive phenotype independent of the local environmental stimuli to which these malignant mature CD4(+) T cells become exposed.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Kasprzycka
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Witkiewicz
authors.forename: Michal
authors.initials: M
authors.lastname: Marzec
authors.forename: Magdalena
authors.initials: M
authors.lastname: Potoczek
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Liu
authors.forename: Hong Yi
authors.initials: HY
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Milone
authors.forename: Samik
authors.initials: S
authors.lastname: Basu
authors.forename: Joanne
authors.initials: J
authors.lastname: Mauger
authors.forename: John K
authors.initials: JK
authors.lastname: Choi
authors.forename: J Todd
authors.initials: JT
authors.lastname: Abrams
authors.forename: J Steven
authors.initials: JS
authors.lastname: Hou
authors.forename: Alain H
authors.initials: AH
authors.lastname: Rook
authors.forename: Eric
authors.initials: E
authors.lastname: Vonderheid
authors.forename: Anders
authors.initials: A
authors.lastname: Woetmann
authors.forename: Niels
authors.initials: N
authors.lastname: Odum
authors.forename: Mariusz A
authors.initials: MA
authors.lastname: Wasik
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000502:physiology*; D018450:Disease Progression; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D016130:Immunophenotyping; D053631:Interleukin Receptor Common gamma Subunit / Q000502:physiology*; D016753:Interleukin-10 / Q000378:metabolism; D019409:Interleukin-15 / Q000502:physiology; D007376:Interleukin-2 / Q000502:physiology; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D015458:Leukemia, T-Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016410:Lymphoma, T-Cell, Cutaneous / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; C508017:IL2RA protein, human; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10