[show abstract][hide abstract] ABSTRACT: The regulation of gene transcription is not simply dependent on the presence or absence of DNA-binding transcription factors that turn genes on or off, but also involves processes determining the ability of transcription factors to gain access to and bind their target DNA. Methylation of DNA cytosine bases leads to the inaccessibility of DNA regulatory elements to their transcription factors by a number of mechanisms. Our understanding of DNA methylation has advanced rapidly in recent years with the identification of an increasingly large number of novel proteins involved in this process. These include methylcytosine-binding proteins as well as additional members of the DNA methyltransferase family. The creation of mice with targeted deletions in a number of genes involved in DNA methylation has further elucidated the functions of many of these proteins. The characterization of complexes that contain proteins known to be involved in DNA methylation has led to the identification of additional proteins, especially those involved in histone deacetylation, indicating that DNA methylation and histone deacetylation very likely act in a synergistic fashion to regulate gene transcription. Finally, the implication of DNA methylation in tumorigenesis and the realization that some congenital diseases are caused by deficiency of proteins involved in DNA methylation has confirmed the importance of this process in regulating gene expression.
Cellular and Molecular Life Sciences CMLS 03/2002; 59(2):241-57. · 5.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: Homozygous deficiency of the second component of complement (C2) is the most common inherited deficiency of complement. Although C2 deficiency has been detected in asymptomatic individuals, patients usually present with either autoimmune disease or recurrent pyogenic infection, particularly due to encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae type b and Neisseria meningitidis. Interestingly, infection is the most common mode of presentation of C2 deficiency in young children (1). An association between C2 deficiency and IgG subclass deficiency has also been previously described. We now report a female child with C2 deficiency that presented at the age of 3 mo with recurrent pneumococcal septicaemia. Although IgG subclass levels were normal, specific IgG responses to vaccination against S. pneumoniae and H. influenzae were significantly impaired.
[show abstract][hide abstract] ABSTRACT: We have recently shown that expression of the enzyme indoleamine 2, 3-dioxygenase (IDO) during murine pregnancy is required to prevent rejection of the allogeneic fetus by maternal T cells. In addition to their role in pregnancy, IDO-expressing cells are widely distributed in primary and secondary lymphoid organs. Here we show that monocytes that have differentiated under the influence of macrophage colony-stimulating factor acquire the ability to suppress T cell proliferation in vitro via rapid and selective degradation of tryptophan by IDO. IDO was induced in macrophages by a synergistic combination of the T cell-derived signals IFN-gamma and CD40-ligand. Inhibition of IDO with the 1-methyl analogue of tryptophan prevented macrophage-mediated suppression. Purified T cells activated under tryptophan-deficient conditions were able to synthesize protein, enter the cell cycle, and progress normally through the initial stages of G1, including upregulation of IL-2 receptor and synthesis of IL-2. However, in the absence of tryptophan, cell cycle progression halted at a mid-G1 arrest point. Restoration of tryptophan to arrested cells was not sufficient to allow further cell cycle progression nor was costimulation via CD28. T cells could exit the arrested state only if a second round of T cell receptor signaling was provided in the presence of tryptophan. These data reveal a novel mechanism by which antigen-presenting cells can regulate T cell activation via tryptophan catabolism. We speculate that expression of IDO by certain antigen presenting cells in vivo allows them to suppress unwanted T cell responses.
Journal of Experimental Medicine 06/1999; 189(9):1363-72. · 13.21 Impact Factor
[show abstract][hide abstract] ABSTRACT: The mechanisms of induction and maintenance of tolerance in self-reactive T cells in the periphery are poorly understood. Current models assume that successful T cell activation only occurs if ligation of the T cell receptor (signal 1) by antigen presenting cells (APCs) is accompanied by a costimulatory signal (signal 2), and that signal 1 in the absence of signal 2 is either ignored or is tolerizing. However, there is also evidence for the existence of macrophages (M phi) capable of suppressing T cell activation both in vitro and in vivo. The possibility of a more actively induced tolerance exists, in which the M phi itself responds to T cell-mediated signals in a tolerogenic fashion. This would help to resolve the paradox that tissue M phi, which act as scavengers of self-antigen, can also act as professional APCs. The ability of tissue macrophages to actively suppress T cells would further underscore the importance of the innate immune system in regulating adaptive immune responses.
International Reviews Of Immunology 02/1999; 18(5-6):515-25. · 5.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: In 1953 Medawar pointed out that survival of the genetically disparate (allogeneic) mammalian conceptus contradicts the laws of tissue transplantation. Rapid T cell-induced rejection of all allogeneic concepti occurred when pregnant mice were treated with a pharmacologic inhibitor of indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme expressed by trophoblasts and macrophages. Thus, by catabolizing tryptophan, the mammalian conceptus suppresses T cell activity and defends itself against rejection.