Abstract
Indoleamine 2,3-dioxygenase (IDO) has been implicated in preventing the fetus from undergoing maternal T cell-mediated immune responses, yet the mechanism underlying these kinds of IDO-mediated immune responses has not been fully elucidated. Since the CD4 molecule plays a central role in the onset and regulation of antigen-specific immune responses, and T cell is sensitive in the absence of tryptophan, we hypothesize that IDO may reduce cell surface CD4 expression. To test this hypothesis, an adenoviral vector-based construct IDO-EGFP was generated and the effect of IDO-EGFP on CD4 expression was determined on recombinant adenoviral infected C8166 and MT-2 cells, by flow cytometry and/or Western blot analysis. The results revealed a significant downregulation of cell membrane CD4 in pAd-IDOEGFP infected cells when compared to that of mock-infected cells or infection with empty vector pAd-EGFP. Further experiments disclosed that either an addition of tryptophan or IDO inhibitor could partly restore CD4 expression in pAd-IDOEGFP infected C8166 cells. Our findings suggest that downregulation of CD4 by IDO might be one of the mechanisms through which IDO regulates T cell-mediated immune responses.
Highlights
Indoleamine 2,3-dioxygenase (IDO) is predominantly expressed in parenchymal tissues such as lungs, gut, and the fetal-maternal unit during pregnancy, as well as in the male epididymis and thymus [1]
The results revealed that the expression of the cell surface CD4 molecule in MT-2 cells infected with pAd-IDOEGFP was reduced when compared with that in mock cells or with cells infected with pAd-enhanced green fluorescent protein (EGFP) (Figure 2D, the upper panel) while similar amounts of β-actin were detected in mock, pAd-EGFP or pAd-IDOEGFP infected
To test the possible mechanism through which IDO mediates the downregulation of CD4 expression on the cell surface, L-tryptophan or IDO inhibitor 1-MT was added to C8166 cells including non-infected, pAd-EGFP and pAd-IDOEGFP infected cells at the time of infection, and at 60 h post infection, the cell surface CD4 molecule was evaluated by flow cytometry and Western blot
Summary
Indoleamine 2,3-dioxygenase (IDO) is predominantly expressed in parenchymal tissues such as lungs, gut, and the fetal-maternal unit during pregnancy, as well as in the male epididymis and thymus [1]. No inflammation, complement deposition or T cell infiltration was found when mice carrying syngeneic fetuses were exposed to IDO inhibitor [8] These data demonstrate that IDO activity protects the fetus from T cell-driven local inflammatory responses to fetal alloantigens. An induction of IDO expression and a progressive loss of T cell function in human immunodeficiency virus type 1(HIV-1)-infected patients [10,16] raises the possibility that IDO may downregulate this cell surface molecule. This led us to hypothesize that the expression of IDO might affect the expression of CD4 on the cell surface.
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