TY - JOUR

T1 - Gamma c-signaling cytokines induce a regulatory T cell phenotype in malignant CD4+ T lymphocytes

AU - Kasprzycka, Monika

AU - Zhang, Qian

AU - Witkiewicz, Agnieszka

AU - Marzec, Michal

AU - Potoczek, Magdalena

AU - Liu, Xiaobin

AU - Wang, Hong Yi

AU - Milone, Michael

AU - Basu, Samik

AU - Mauger, Joanne

AU - Choi, John K

AU - Abrams, J Todd

AU - Hou, J Steven

AU - Rook, Alain H

AU - Vonderheid, Eric

AU - Woetmann, Anders

AU - Ødum, Niels

AU - Wasik, Mariusz A

N1 - Keywords: CD4-Positive T-Lymphocytes; Cell Line, Tumor; Cytokines; Disease Progression; Forkhead Transcription Factors; Humans; Immunophenotyping; Interleukin Receptor Common gamma Subunit; Interleukin-10; Interleukin-15; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Leukemia, T-Cell; Lymphoma, T-Cell, Cutaneous; Signal Transduction; Skin Neoplasms; T-Lymphocytes, Regulatory

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

M3 - Journal article

C2 - 18684941

VL - 181

SP - 2506

EP - 2512

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 4

ER -