TGF-β1 dampens the susceptibility of dendritic cells to environmental stimulation, leading to the requirement for danger signals for activation

Tomoyuki Ohtani, Masato Mizuashi, Satoshi Nakagawa, Yoshinori Sasaki, Taku Fujimura, Ryuhei Okuyama, Setsuya Aiba

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

In contrast to its favourable effects on Langerhans cell (LC) differentiation, transforming growth factor (TGF)-β1 has been reported to prevent dendritic cells from maturing in response to tumour necrosis factor (TNF)-α, interleukin (IL)-1β, or lipopolysaccharide (LPS). We first characterized the effects of TGF-β1 on dendritic cell function by testing the response of TGF-β1-treated monocyte-derived dendritic cells (MoDCs) to maturation stimuli that LCs receive in the epidermis, namely, haptens, ATP and ultraviolet (UV). TGF-β1 treatment, which augmented E-cadherin and down-regulated dendritic cell-specific ICAM3-grabbing non-integrin on MoDCs, significantly suppressed their CD86 expression and hapten-induced expression of IL-1β and TNF-α mRNA and protein. As TGF-β1-treated MoDCs lacked Langerin expression, we demonstrated the suppressive effects of TGF-β1 on haematopoietic progenitor cell-derived dendritic cells expressing both CD1a and Langerin. These suppressive effects of TGF-β1 increased with the duration of treatment. Furthermore, TGF-β1-treated MoDCs became resistant to apoptosis/necrosis induced by high hapten, ATP or UV doses. This was mainly attributable to dampened activation of p38 mitogen-activated protein kinase (MAPK) in TGF-β1-treated MoDCs. Notably, although ATP or hapten alone could only induce CD86 expression weakly and could not augment the allogeneic T-cell stimulatory function of TGF-β1-treated MoDCs, ATP and hapten synergized to stimulate these phenotypic and functional changes. Similarly, 2,4-dinitro, 1-chlorobenzene (DNCB) augmented the maturation of TGF-β1-treated MoDCs upon co-culture with a keratinocyte cell line, in which ATP released by the hapten-stimulated keratinocytes synergized with the hapten to induce their maturation. These data may suggest that TGF-β1 protects LCs from being overactivated by harmless environmental stimulation, while maintaining their ability to become activated in response to danger signals released by keratinocytes.

Original languageEnglish
Pages (from-to)485-499
Number of pages15
JournalImmunology
Volume126
Issue number4
DOIs
Publication statusPublished - 2009 Apr

Keywords

  • Antigen-presenting cells
  • Apoptosis
  • Costimulatory molecules
  • Dendritic cells
  • Langerhans cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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