Abstract
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
Substances
-
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