title: Transforming growth factor β signaling controls activities of human intestinal CD8(+)T suppressor cells.
abstract: OBJECTIVE
  In healthy individuals, interactions between intestinal epithelial cells and lamina propria lymphocytes give rise to a population of CD8(+) T cells with suppressor functions (Ts cells). Disruption of Ts cell activities can lead to mucosal inflammation. We investigated what factors were required for expansion of the Ts cell population or loss of their activity in patients with Crohn's disease (CD).
  
  
  METHODS
  We developed a method to generate Ts cell lines from freshly isolated lamina propria lymphocytes from patients with ulcerative colitis (UC), patients with CD, or healthy individuals (controls). Cells were stimulated with a monoclonal antibody against CD3, interleukin (IL)-7, and IL-15. After 14 days in culture, CD8(+)T cells were purified and cultured with IL-7 and IL-15. The resulting Ts cells were analyzed for suppressor activity, expression of surface markers, and cytokine secretion profiles. RNA was isolated from the 3 groups of Ts cells and used in microarray analyses.
  
  
  RESULTS
  Ts cells from patients with UC and controls suppressed proliferation of CD4(+) T cells; the suppression required cell contact. In contrast, Ts cells from patients with CD had a reduced capacity to suppress CD4(+) T-cell proliferation. The difference in suppressive ability was not associated with surface or intracytoplasmic markers or secretion of cytokines. Microarray analysis identified changes in expression of genes regulated by transforming growth factor (TGF)-β that were associated with the suppressive abilities of Ts cells. We found that TGF-β or supernatants from Ts cells of patients with CD reduced the suppressor activity of control Ts cells.
  
  
  CONCLUSIONS
  Ts cells isolated from patients with CD have a reduced ability to suppress proliferation of CD4(+)T cells compared with control Ts cells. TGF-β signaling reduces the suppressor activity of Ts cells.
authors.affiliation: Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Keren M
authors.initials: KM
authors.lastname: Rabinowitz
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Chen
authors.forename: Zara
authors.initials: Z
authors.lastname: Hovhannisyan
authors.forename: David
authors.initials: D
authors.lastname: Chiang
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Berin
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dahan
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.forename: Avi
authors.initials: A
authors.lastname: Ma'ayan
authors.forename: Lloyd
authors.initials: L
authors.lastname: Mayer
mesh_terms: D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D002469:Cell Separation; D020869:Gene Expression Profiling; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology*; D007422:Intestines / Q000276:immunology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma