Abstract
Studies in an in vitro model of cutaneous T-cell lymphoma (CTCL) demonstrated that CTCL cell proliferation is stimulated by direct contact with autologous, immature dendritic cells (DCs), suggesting that CD4(+) CTCL cell division is driven by antigens presented by DC major histocompatibility complex (MHC) class 2. We now report that the T-cell receptor (TCR) of the CD4(+) CTCL cells is triggered after interaction with DCs loaded with apoptotic CTCL cells, as shown by reduced membrane expression of CD3 and the TCR, up-regulation of cytotoxic T lymphocyte antigen-4 (CTLA-4), and calcium mobilization. CTCL cells adopt a T-regulatory (Treg) phenotype expressing CD25/CTLA-4 and FoxP3 and secreting interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta). Treg CTCL cells suppress normal T-cell antigen-driven secretion of IL-2 and interferon-gamma (IFN-gamma). Blocking DC MHC class 2 expression or transport inhibited CTCL cell adoption of a Treg phenotype. Allogeneic CTCL cells or normal CD4 T cells served as sources of apoptotic material for CTCL cell conversion to a Treg phenotype. Conversion of CTCL cells to Treg cells may explain the anergic, immunosuppressive nature of the malignancy.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antibodies, Blocking / pharmacology
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Antigens / pharmacology
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Antigens, CD
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Antigens, Differentiation / biosynthesis
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Antigens, Differentiation / metabolism
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Apoptosis / immunology
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CTLA-4 Antigen
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Calcium / metabolism
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Cell Proliferation
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Cell Transformation, Neoplastic / immunology*
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology*
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Cytokines / antagonists & inhibitors
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Cytokines / biosynthesis
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Dendritic Cells / pathology
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Dose-Response Relationship, Immunologic
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Histocompatibility Antigens Class II / immunology
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Histocompatibility Antigens Class II / metabolism
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Humans
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Immunophenotyping
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Interleukin-10 / metabolism
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Lymphocyte Activation / immunology
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Lymphoma, T-Cell, Cutaneous / immunology*
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Lymphoma, T-Cell, Cutaneous / metabolism
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Lymphoma, T-Cell, Cutaneous / pathology*
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Skin Neoplasms / immunology*
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Skin Neoplasms / metabolism
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Skin Neoplasms / pathology*
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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T-Lymphocytes, Regulatory / pathology*
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Transforming Growth Factor beta / metabolism
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Tumor Cells, Cultured
Substances
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Antibodies, Blocking
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Antigens
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Antigens, CD
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Antigens, Differentiation
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CTLA-4 Antigen
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CTLA4 protein, human
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Cytokines
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Histocompatibility Antigens Class II
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Transforming Growth Factor beta
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Interleukin-10
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Calcium