Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase.
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 CD8alpha. 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 gamma (IFNgamma)-receptor-deficient mice were effective in promoting IDO-dependent T cell suppression following CTLA4-Ig exposure in vivo, indicating that IFNgamma 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.
Mellor
Andrew L
AL
Department of Medicine, Program in Molecular Immunology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120, 15th Street, Augusta, GA 30912-2600, USA. amellor@mcg.edu
Chandler
Phillip
P
Baban
Babak
B
Hansen
Anna M
AM
Marshall
Brendan
B
Pihkala
Jeanene
J
Waldmann
Herman
H
Cobbold
Stephen
S
Adams
Elizabeth
E
Munn
David H
DH
D000069594:Abatacept; D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology*; D005434:Flow Cytometry; D018796:Immunoconjugates / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000276:immunology / Q000378:metabolism*
D018122:B7-1 Antigen; D018796:Immunoconjugates; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D000069594:Abatacept; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase