Immunoregulatory effects of indoleamine 2, 3-dioxygenase in transplantation.
ABSTRACT Indoleamine 2, 3-dioxygenase (IDO) is an intracellular hemeprotein enzyme which catalyses the essential amino acid tryptophan. Accumulating evidence has demonstrated that tryptophan depletion and its toxic metabolites expression in tissue microenvironment can suppress local allogeneic T cell proliferation and activation. Ever since the discovery that IDO was involved in the maintenance of fetal-maternal tolerance, numerous studies have confirmed that IDO is a potent regulator of immune cell function. Importantly, IDO+dendritic cells (DCs) might interact with regulatory T cells (Tregs) to form an immunomodulatory network to promote immune tolerance induction. Moreover, it has been reported that overexpression of IDO in transplanted organs can prolong allograft survival, suggesting a possible peripheral tolerogenic pathway with important implications in transplantation. However, the underlying mechanism for the beneficial effects of IDO in transplantation remains unclear. In this review, we attempt to summarize our current understandings about IDO as a mediator of immunity in transplantation and provide an overview of IDO as a new paradigm in transplantation.
Article: Human cytomegalovirus IE1 protein elicits a type II interferon-like host cell response that depends on activated STAT1 but not interferon-γ.[show abstract] [hide abstract]
ABSTRACT: Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-γ and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-γ-responsive promoters. However, neither synthesis nor secretion of IFN-γ or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity.PLoS Pathogens 04/2011; 7(4):e1002016. · 9.13 Impact Factor