Transforming growth factor β signaling controls activities of human intestinal CD8+T suppressor cells

Keren M. Rabinowitz, Yuanyuan Wang, Edward Y. Chen, Zara Hovhannisyan, David Chiang, M. Cecilia Berin, Stephanie Dahan, Damien Chaussabel, Avi Ma'Ayan, Lloyd Mayer

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Abstract

Background & Aims: 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.

Original languageEnglish
Pages (from-to)601-612.e1
JournalGastroenterology
Volume144
Issue number3
DOIs
Publication statusPublished - Mar 2013

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Keywords

  • Immune Regulation
  • Inflammatory Bowel Disease
  • Regulatory T Cells
  • Treg Cells

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Rabinowitz, K. M., Wang, Y., Chen, E. Y., Hovhannisyan, Z., Chiang, D., Berin, M. C., Dahan, S., Chaussabel, D., Ma'Ayan, A., & Mayer, L. (2013). Transforming growth factor β signaling controls activities of human intestinal CD8+T suppressor cells. Gastroenterology, 144(3), 601-612.e1. https://doi.org/10.1053/j.gastro.2012.12.001