Gamma c-signaling cytokines induce a regulatory T cell phenotype in malignant CD4+ T lymphocytes.
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.
Kasprzycka
Monika
M
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Zhang
Qian
Q
Witkiewicz
Agnieszka
A
Marzec
Michal
M
Potoczek
Magdalena
M
Liu
Xiaobin
X
Wang
Hong Yi
HY
Milone
Michael
M
Basu
Samik
S
Mauger
Joanne
J
Choi
John K
JK
Abrams
J Todd
JT
Hou
J Steven
JS
Rook
Alain H
AH
Vonderheid
Eric
E
Woetmann
Anders
A
Odum
Niels
N
Wasik
Mariusz A
MA
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
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