Allostimulatory activity of bone marrow-derived plasmacytoid dendritic cells is independent of indoleamine dioxygenase but regulated by inducible costimulator ligand expression

Hum Immunol. 2009 May;70(5):313-20. doi: 10.1016/j.humimm.2009.01.021. Epub 2009 Feb 3.


We investigated the role of two key immunoregulatory molecules, indoleamine dioxygenase (IDO) and inducible costimulator ligand (ICOSL), in determining the function of bone marrow (BM)-derived plasmacytoid (p)DC, which offer the potential for therapy of allograft rejection. pDC generated from BM of wild-type (WT) or IDO knockout (KO) C57BL/6 mice were used to stimulate T-cell proliferation and interferon-gamma (IFN-gamma) production in response to alloantigen (alloAg) via the direct or indirect pathways. In some experiments, pDC were first activated by exposure to CpG +/- CTLA4Ig for IDO induction via B7 ligation. Although IDO KO pDC induced enhanced T-cell responses compared with WT pDC, the use of the IDO inhibitor 1-methyltryptophan (1-MT) demonstrated that the inferior stimulatory capacity of WT pDC was not caused by the production of functional IDO, even under IDO-inducing conditions. The DNAX-activating protein of 12 kDa (DAP12), which inhibits functional IDO expression, was expressed in BM-pDC. DAP12 silencing increased the T-cell stimulatory capacity of WT pDC, but only in the presence of 1-MT. Compared with WT pDC, activated IDO KO DC expressed much lower levels of ICOSL. Moreover, when ICOSL was blocked on WT pDC, T-cell proliferation resembled that induced by IDO KO pDC, and interleukin (IL)-10 secretion in MLR was markedly decreased. These findings implicate ICOSL-induced IL-10, but not IDO in the regulation of BM-derived pDC function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antigens, CD / pharmacology
  • Antigens, Differentiation, T-Lymphocyte / immunology
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • B7-2 Antigen / immunology
  • B7-2 Antigen / metabolism
  • CTLA-4 Antigen
  • Cell Proliferation / drug effects
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Inducible T-Cell Co-Stimulator Ligand
  • Inducible T-Cell Co-Stimulator Protein
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Interleukin-10 / immunology*
  • Interleukin-10 / metabolism
  • Interleukin-4 / immunology
  • Interleukin-4 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proteins / immunology*
  • Proteins / metabolism
  • RNA, Small Interfering / immunology
  • RNA, Small Interfering / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Tryptophan / analogs & derivatives
  • Tryptophan / pharmacology


  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • B7-2 Antigen
  • CTLA-4 Antigen
  • Cd86 protein, mouse
  • Ctla4 protein, mouse
  • Icos protein, mouse
  • Icosl protein, mouse
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Inducible T-Cell Co-Stimulator Ligand
  • Inducible T-Cell Co-Stimulator Protein
  • Proteins
  • RNA, Small Interfering
  • Tyrobp protein, mouse
  • Interleukin-10
  • Interleukin-4
  • Interferon-gamma
  • Tryptophan
  • 1-methyltryptophan