CTLA-4–Ig regulates tryptophan catabolism in vivo

Abstract

Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) plays a critical role in peripheral tolerance. However, regulatory pathways initiated by the interactions of CTLA-4 with B7 counterligands expressed on antigen-presenting cells are not completely understood. We show here that long-term survival of pancreatic islet allografts induced by the soluble fusion protein CTLA-4–immunoglobulin (CTLA-4–Ig) is contingent upon effective tryptophan catabolism in the host. In vitro, we show that CTLA-4–Ig regulates cytokine-dependent tryptophan catabolism in B7-expressing dendritic cells. These data suggest that modulation of tryptophan catabolism is a means by which CTLA-4 functions in vivo and that CTLA-4 acts as a ligand for B7 receptor molecules that transduce intracellular signals.

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Figure 1: Soluble CTLA-4 initiates tryptophan catabolism in a dose- and time-dependent fashion.
Figure 2: B7 expression is required for IDO activation by CTLA-4–Ig.
Figure 3: Soluble CTLA-4 induces transcriptional expression of Ifng and production of the IFN-γ protein.
Figure 4: Production of IFN-γ and recruitment of STAT1 are required for IDO activation by soluble CTLA-4.

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Acknowledgements

Supported in part by the Juvenile Diabetes Research Foundation International (U. G.) and the Italian Association for Cancer Research (P. P.). We thank A. L. Mellor for the generous gift of IDO-specific reagents.

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Correspondence to Ursula Grohmann.

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Grohmann, U., Orabona, C., Fallarino, F. et al. CTLA-4–Ig regulates tryptophan catabolism in vivo. Nat Immunol 3, 1097–1101 (2002). https://doi.org/10.1038/ni846

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