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

Blood. 2005 Feb 15;105(4):1640-7. doi: 10.1182/blood-2004-06-2181. Epub 2004 Oct 28.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibodies, Blocking / pharmacology
  • Antigens / pharmacology
  • Antigens, CD
  • Antigens, Differentiation / biosynthesis
  • Antigens, Differentiation / metabolism
  • Apoptosis / immunology
  • CTLA-4 Antigen
  • Calcium / metabolism
  • Cell Proliferation
  • Cell Transformation, Neoplastic / immunology*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology*
  • Cytokines / antagonists & inhibitors
  • Cytokines / biosynthesis
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dendritic Cells / pathology
  • Dose-Response Relationship, Immunologic
  • Histocompatibility Antigens Class II / immunology
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Immunophenotyping
  • Interleukin-10 / metabolism
  • Lymphocyte Activation / immunology
  • Lymphoma, T-Cell, Cutaneous / immunology*
  • Lymphoma, T-Cell, Cutaneous / metabolism
  • Lymphoma, T-Cell, Cutaneous / pathology*
  • 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

Substances

  • Antibodies, Blocking
  • Antigens
  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cytokines
  • Histocompatibility Antigens Class II
  • Transforming Growth Factor beta
  • Interleukin-10
  • Calcium