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The Directive Role of Regulatory T Cells in Orchestrating Tolerance By Dendritic Cells

Posted on: Thursday, 17 June 2004, 06:00 CDT

Regulatory (TR)T cells are involved in the maintenance of selftolerance and have the potential for preventing allograft rejection and treating chronic inflammatory diseases. Although some of the inhibitory effects of TR seem to be mediated by the production of immunosuppressive cytokines, other mechanisms, mostly operative in noninflammatory settings, seem to involve direct interactions of TR cells with responding T lymphoytes or anttigen- presenting-cells (APCs). Among the latter, dendritic cells (DCs) contribute crucially to immunoregulation in transplantation and autoimmunity. We have previously showed that functional expression of indoleamine 2,3 dioxygenase (IDO) in DC subsets correlates with the appearance of a tolerogenic phenotype in these cells. IDO catalyzes the oxidative cleavage of the indole ring of several important regulatory molecules, including tryptophan, and initiates the production of neuroactive and immunoregulatory metabolites, collectively known as kynurenines. Interferons (IFNs), released by leukocytes and lymphocytes, will act on specific receptors to trigger IDO induction in certain cell types such as DCs and macrophages. By locally depleting tryptophan and increasing proapoptotic kynurenines, IDO expressed by DCs greatly affects T- cell proliferation and survival by promoting activation-induced cell death. IDO induction in DCs could be a common mechanism of deletional tolerance driven by (T^sub R^) cells involved in the maintenance of immune homeostasis. T^sub R^ constitutively express cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), which has a key role in T-cell-mecliatecl dominant immunological self- tolerance. We have recently proposed a novel model of tolerance induction by BT-clependent signaling in DCs. Using an experimental system of allogeneic islet transplant tolerance, we have shown that B7 engagement by a soluble form of CTLA-4 conditions the DCs to produce IFN[gamma] that is able to promote IDO induction. This enables long-term transplant survival and tolerance as a result of lymphocyte apoptosis. Recently, we have demonstrated that T^sub R^ cells initiate tryptophan catabolism in DCs through a CTLA-4- dependent mechanism, his process requires B7 expression and cytokine production by the DCs. These data suggest that localized control of tryptophan catabolism in specific tissue microenvironments may contribute to the induction and maintenance of peripheral tolerance.

F. Fallarino, U. Grohmann, C. Orabona, C. Vacca, R. Bianchi, M.L. Belladonna, C. Volpi, M.C. Fioretti, P. Puccetti

Department of Experimental Medicine and Biochemical Science, Section of Pharmacology, University of Perugia, Perugia, Italy

Copyright Edizioni Minerva Medica Mar 2004

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