TY - JOUR
T1 - A minor population of splenic dendritic cells expressing CD19 mediates IDO-dependent T cell suppression via type I IFN signaling following B7 ligation
AU - Baban, Babak
AU - Hansen, Anna M.
AU - Chandler, Phillip R.
AU - Manlapat, Anna
AU - Bingaman, Adam
AU - Kahler, David J.
AU - Munn, David H.
AU - Mellor, Andrew L.
N1 - Funding Information:
We thank the manager of the MCG Flow Cytometry Core facility, Jeanine Pihkala, for expert assistance with flow cytometry and Anita Wylds, Doris McCool and Erika Thompson for technical assistance with multiple aspects of studies reported here. This work was supported by NIH grants to A.L.M. (HD41187, AI063402) and D.H.M. (CA103320, CA096651).
PY - 2005/7
Y1 - 2005/7
N2 - By ligating CD80/CD86 (B7) molecules, the synthetic immunomodulatory reagent CTLA4-Ig (soluble synthetic CTLA4 fusion protein) induces expression of the enzyme indoleamine 2,3-dioxygenase (IDO) in some dendritic cells (DCs), which acquire potent T cell regulatory functions as a consequence. Here we show that this response occurred exclusively in a population of splenic DCs co-expressing the marker CD19. B7 ligation induced activation of the transcription factor signal transducer and activator of transcription (STAT1) in sorted CD19+, but not CD19NEG, DCs. STAT1 activation occurred even when DCs lacked receptors for type II IFN (IFNγ); however, STAT1 activation and IDO up-regulation were not observed when DCs lacked receptors for type I IFN (IFNαβ). Thus, IFNα, but not IFNγ, signaling was essential for STAT1 activation and IDO up-regulation in CD19+ DCs following B7 ligation. Consistent with these findings, B7 ligation also induced sorted CD19+, but not CD19NEG, DCs to express IFNα. Moreover, recombinant IFNα induced CD19+, but not CD19NEG, DCs to mediate IDO-dependent T cell suppression, showing that IFNα signaling could substitute for upstream signals from B7. These data reveal that a minor population of splenic DCs expressing the CD19 marker is uniquely responsive to B7 ligation, and that IFNα-mediated STAT1 activation is an essential intermediary signaling pathway that promotes IDO induction in these DCs. Thus, CD19+ DCs may be a target for regulatory T cells expressing surface CTLA4, and may suppress T cell responses via induction of IDO.
AB - By ligating CD80/CD86 (B7) molecules, the synthetic immunomodulatory reagent CTLA4-Ig (soluble synthetic CTLA4 fusion protein) induces expression of the enzyme indoleamine 2,3-dioxygenase (IDO) in some dendritic cells (DCs), which acquire potent T cell regulatory functions as a consequence. Here we show that this response occurred exclusively in a population of splenic DCs co-expressing the marker CD19. B7 ligation induced activation of the transcription factor signal transducer and activator of transcription (STAT1) in sorted CD19+, but not CD19NEG, DCs. STAT1 activation occurred even when DCs lacked receptors for type II IFN (IFNγ); however, STAT1 activation and IDO up-regulation were not observed when DCs lacked receptors for type I IFN (IFNαβ). Thus, IFNα, but not IFNγ, signaling was essential for STAT1 activation and IDO up-regulation in CD19+ DCs following B7 ligation. Consistent with these findings, B7 ligation also induced sorted CD19+, but not CD19NEG, DCs to express IFNα. Moreover, recombinant IFNα induced CD19+, but not CD19NEG, DCs to mediate IDO-dependent T cell suppression, showing that IFNα signaling could substitute for upstream signals from B7. These data reveal that a minor population of splenic DCs expressing the CD19 marker is uniquely responsive to B7 ligation, and that IFNα-mediated STAT1 activation is an essential intermediary signaling pathway that promotes IDO induction in these DCs. Thus, CD19+ DCs may be a target for regulatory T cells expressing surface CTLA4, and may suppress T cell responses via induction of IDO.
KW - CTLA4-lg
KW - Dendritic cells
KW - I cell suppression
KW - Interferon
KW - STAT1
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U2 - 10.1093/intimm/dxh271
DO - 10.1093/intimm/dxh271
M3 - Article
C2 - 15967784
AN - SCOPUS:26444489716
SN - 0953-8178
VL - 17
SP - 909
EP - 919
JO - International Immunology
JF - International Immunology
IS - 7
ER -