Interplay between CD45RA+ regulatory T cells and TNF-alpha in the regulation of human Th17 differentiation

Int Immunol. 2010 Apr;22(4):237-44. doi: 10.1093/intimm/dxp130. Epub 2010 Feb 24.


The balance between effector CD4(+) T cells secreting IL-17 (T(h)17) and regulatory T cells (Treg) plays an important role in autoimmune disorders that include rheumatoid arthritis (RA) and Crohn's disease. Tumor necrosis factor (TNF)-alpha is a key pro-inflammatory cytokine that contributes to disease pathogenesis. We investigated the interplay between CD45RA(+) Treg and TNF-alpha in the regulation of human T(h)17 differentiation. We found that CD45RA(+) Treg promoted while TNF-alpha inhibited naive CD4(+) T-cell differentiation into IL-17 and CCL20 co-expressing T(h)17 cells without influencing their IL-22 release. Unexpectedly, CD45RA(+) Treg depletion abrogated TNF-alpha suppressive function. Finally, dendritic cell-derived TNF-alpha suppressed the development of IL-17(+)CCL20(+) expressing T(h)17 cells. In conclusion, CD45RA(+) Treg positively governs human T(h)17 development, which is impaired by TNF-alpha. We propose that TNF-alpha may represent a negative feedback mechanism to control IL-17/CCL20- but not IL-22-associated autoimmune pathologies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmune Diseases / immunology*
  • Cell Differentiation
  • Cells, Cultured
  • Chemokine CCL20 / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Humans
  • Interleukin-17 / biosynthesis
  • Interleukins / biosynthesis
  • Leukocyte Common Antigens / biosynthesis
  • Leukocyte Common Antigens / immunology*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Tumor Necrosis Factor-alpha / immunology*


  • CCL20 protein, human
  • Chemokine CCL20
  • Interleukin-17
  • Interleukins
  • Tumor Necrosis Factor-alpha
  • Leukocyte Common Antigens
  • interleukin-22