Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase

Andrew L. Mellor, Phillip Chandler, Babak Baban, Anna M. Hansen, Brendan Marshall, Jeanene Pihkala, Herman Waldmann, Stephen Cobbold, Elizabeth Adams, David H. Munn

Research output: Contribution to journalArticle

241 Scopus citations

Abstract

Murine dendritic cells (DCs) expressing indoleamine 2,3 dioxygenase (IDO) catabolize tryptophan and can suppress T cell responses elicited in vivo. Here, we identify specific subsets of splenic (CD11c+) dendritic cells competent to mediate IDO-dependent T cell suppression following CTLA4-mediated ligation of B7 molecules. IDO-competent DC subsets acquired potent and dominant T cell suppressive properties as a consequence of IDO up-regulation, as they blocked the ability of T cells to respond to other stimulatory DCs in the same cultures. Soluble CTLA4 (CTLA4-Ig) and cloned CTLA4+ regulatory T cells (Tr1D1) up-regulated IDO selectively in DC subsets co-expressing B220 or CD82a. The ability of Tr1D1 T cells to suppress CD8+ T cell responses was completely dependent on their ability to induce tryptophan catabolism in DCs. Selective IDO up-regulation in DCs did not inhibit T cell activation, but prevented T cell clonal expansion due to rapid death of activated T cells. T cell responses were restored by genetic or pharmacologic inhibition of IDO enzyme activity, or by adding excess tryptophan. DCs from interferon γ (IFNγ)-receptor-deficient mice were effective in promoting IDO-dependent T cell suppression following CTLA4-Ig exposure in vivo, indicating that IFNγ signaling was not necessary for IDO up-regulation in this model. These findings suggest that IDO-competent DCs provide a regulatory bridge, mediated by CTLA4-B7 engagement, between certain regulatory T cell subsets and naive responder T cells.

Original languageEnglish (US)
Pages (from-to)1391-1401
Number of pages11
JournalInternational Immunology
Volume16
Issue number10
DOIs
StatePublished - Oct 1 2004

Keywords

  • Dendritic cells
  • IDO
  • Mice
  • Suppression
  • T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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