Activating NK-cell receptors co-stimulate CD4(+)CD28(-) T cells in patients with rheumatoid arthritis

Eur J Immunol. 2010 Feb;40(2):378-87. doi: 10.1002/eji.200939399.

Abstract

Effector T-cell responses can be modulated by competing positive or negative signals transduced by NK-cell receptors (NKR). In the CD4(+) T-cell population, the expression of NKR is primarily found in the CD4(+)CD28(-) T-cell subset, also known as CD28(null) T cells. These T cells are frequently found in rheumatoid arthritis (RA) and other inflammatory disorders, suggesting that signaling through NKR may play a role in the autoimmune reaction. Here we aimed to dissect the phenotype and function of NKR-expressing CD4(+)CD28(-) T cells in patients with RA. By analyzing a broad array of NKR on CD4(+)CD28(-) T cells we found a significant expression of the co-activating receptors 2B4 (CD244), DNAM-1 (CD226), and CRACC. Pair-wise ligations of 2B4 with DNAM-1 and/or NKG2D lead to increased effector functions of primary CD4(+)CD28(-) T cells to suboptimal levels of anti-CD3 stimulation. Using multi-parameter flow cytometry, we demonstrate that such co-ligation led to an increased magnitude in overall responsiveness without changing qualitative aspects of the response. Altogether these results demonstrate a pattern of additive effects in NKR-mediated functional modulation of CD4(+)CD28(-) T cells in RA. This may have consequences for the inflammatory responses imposed by these cells, thus influencing disease manifestations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antibodies / immunology
  • Antibodies / pharmacology
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / genetics
  • Antigens, Differentiation, T-Lymphocyte / immunology
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / pathology
  • CD28 Antigens / metabolism
  • CD3 Complex / immunology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cells, Cultured
  • Female
  • Flow Cytometry
  • Humans
  • Interferon-gamma / metabolism
  • Male
  • Middle Aged
  • Protein Binding
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism
  • Receptors, Natural Killer Cell / genetics
  • Receptors, Natural Killer Cell / immunology*
  • Receptors, Natural Killer Cell / metabolism
  • Signal Transduction / immunology*
  • Signaling Lymphocytic Activation Molecule Family
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antibodies
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD226 antigen
  • CD244 protein, human
  • CD28 Antigens
  • CD3 Complex
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
  • SLAMF7 protein, human
  • Signaling Lymphocytic Activation Molecule Family
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma