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Modulation of tryptophan catabolism by regulatory T cells

Abstract

Regulatory T (TR) cells manifest constitutive expression of cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), but the function of CTLA-4 in mediating the regulatory function of TR cells is unclear. We show here that mouse CD4+CD25+ cells, either resting or induced to overexpress CTLA-4 by treatment with antibody to CD3, initiated tryptophan catabolism in dendritic cells through a CTLA-4-dependent mechanism. This process required B7 expression and cytokine production by the dendritic cells. In contrast, TR cells cultured in the presence of bacterial lipopolysaccharide induced tryptophan catabolism by dendritic cells in a CTLA-4-independent but cytokine-dependent way. Thus, regulation of immunosuppressive tryptophan catabolism in dendritic cells might represent a major mechanism of action of TR cells.

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Figure 1: Cytofluorometric analysis of Jurkat cells stained with anti-CTLA-4.
Figure 2: Surface expression of CTLA-4 correlates with induction of IFN-γ and tryptophan catabolism in mouse DCs.
Figure 3: Cytofluorometric analysis of CD4+CD25 and CD4+CD25+ cells stained with anti-CTLA-4.
Figure 4: CD4+CD25+ T cells induce IFN-γ production and tryptophan catabolism in DCs.
Figure 5: B7 expression and IFN-γ production by DCs are required for modulation of tryptophan catabolism by TR cells.
Figure 6: CD4+CD25+ cells prime DCs for tolerogenic presentation of a synthetic peptide in vivo through an IDO-dependent mechanism.

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Acknowledgements

We thank M.P. Colombo for the gift of genetically deficient mice. Supported by the Italian Association for Cancer Research.

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Correspondence to Paolo Puccetti.

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Fallarino, F., Grohmann, U., Hwang, K. et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 4, 1206–1212 (2003). https://doi.org/10.1038/ni1003

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