Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells

• Published in: Blood 2005-02, Vol.105 (4), p.1640-1647
• Main Authors: Berger, Carole L., Tigelaar, Robert, Cohen, Justine, Mariwalla, Kavita, Trinh, Jennifer, Wang, Nianci, Edelson, Richard L.
• Format: Article
• Language: English
• Subjects: Antibodies, Blocking - pharmacology; Antigens - pharmacology; Antigens, CD; Antigens, Differentiation - biosynthesis; Antigens, Differentiation - metabolism; Apoptosis - immunology; Biological and medical sciences; Calcium - metabolism; Cell Proliferation; Cell Transformation, Neoplastic - immunology; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; CTLA-4 Antigen; Cytokines - antagonists & inhibitors; Cytokines - biosynthesis; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - pathology; Dose-Response Relationship, Immunologic; Hematologic and hematopoietic diseases; Histocompatibility Antigens Class II - immunology; Histocompatibility Antigens Class II - metabolism; Humans; Immunophenotyping; Interleukin-10 - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocyte Activation - immunology; Lymphoma, T-Cell, Cutaneous - immunology; Lymphoma, T-Cell, Cutaneous - metabolism; Lymphoma, T-Cell, Cutaneous - pathology; Medical sciences; Skin Neoplasms - immunology; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; Transforming Growth Factor beta - metabolism; Tumor Cells, Cultured
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-06-2181

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-β (TGF-β). Treg CTCL cells suppress normal T-cell antigen-driven secretion of IL-2 and interferon-γ (IFN-γ). 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. (Blood. 2005;105:1640-1647)